Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4245—Oxadiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
  • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
  • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
  • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
  • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
  • A61K47/6859—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from liver or pancreas cancer cell
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
  • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
  • A61K47/6869—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
  • C07K16/2812—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
  • C07K5/06052—Val-amino acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/06—Linear peptides containing only normal peptide links 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
  • C07K2317/565—Complementarity determining region [CDR]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

• the present application relates to new binder-drug conjugates (ADCs) of N,N-dialkylauristatins that are directed against the target mesothelin, to active metabolites of these ADCs, to processes for preparing these ADCs, to the use of these ADCs for treating and/or preventing illnesses, and also to the use of these ADCs for producing medicaments for treating and/or preventing illnesses, more particularly hyperproliferative and/or angiogenic diseases such as, for example, cancer diseases.
• ADCs binder-drug conjugates
• Such treatments may be practised as a monotherapy or else in combination with other medicaments or further therapeutic measures.
• Cancer diseases are the consequence of uncontrolled cell growth in a wide variety of tissues. In many cases the new cells penetrate existing tissue (invasive growth), or they metastase into remote organs. Cancer diseases occur in a wide variety of organs, and the illnesses often progress in a tissue-specific manner.
• the designation “cancer disease” as a generic term therefore describes a large group of defined diseases of different organs, tissues and cell types.
• tumours may be able to be removed by surgical and radiotherapeutic measures. Metastasized tumours can generally only be given palliative therapy by means of chemotherapeutic agents. The objective in that case is to achieve the optimum combination of improving quality of life and prolonging remaining lifetime.
• chemotherapeutic agents which are presently administered parenterally are often not target-directed at the tumour tissue or the tumour cells, but instead, as a result of their systemic administration, are distributed non-specifically within the body, hence including at locations at which exposure to the drug is undesirable, such as in healthy cells, tissues and organs, for example. This may lead to unwanted side-effects and even to serious effects of general toxicity, which then often greatly limit the therapeutically useful dose range of the drug, or necessitate complete cessation of medication.
• Monoclonal antibodies are suitable for the target-directed addressing of tumour tissue and tumour cells.
• the significance of such antibodies for the clinical treatment of cancer diseases has seen a considerable general increase in recent years, based on the activity of such agents as trastuzumab (Herceptin), rituximab (Rituxan), cetuximab (Erbitux) and bevacizumab (Avastin), which have since been approved for the therapy of individual, specific tumour diseases [see e.g. G. P. Adams and L. M. Weiner, Nat. Biotechnol. 23, 1147-1157 (2005)].
• immunoconjugates such as, for example, the aforementioned ADCs, in which an internalizing antibody directed against a tumour-associated antigen is joined covalently via a linking unit (“linker”) to a cytotoxic agent.
• linker to a cytotoxic agent.
• binders from the small-molecule drug sphere can be used as binders which bind selectively to a specific target location (“target”), such as to a receptor, for example [see e.g. E. Ruoslahti et al., Science 279, 377-380 (1998); D. Karkan et al., PLoS ONE 3 (6), e2469 (Jun. 25, 2008)].
• target such as to a receptor
• conjugates of cytotoxic drug and addressing ligand that exhibit a defined cleavage point between ligand and drug for the release of the drug.
• a “predetermined break point” of this kind may exist, for example, within a peptide chain which can be cleaved selectively at a particular site by a specific enzyme at the location of action [see e.g. R. A. Firestone and L. A. Telan, US Patent Application US 2002/0147138].
• HERCEPTIN® and Erbitux® are used successfully in the treatment of HER2-positive breast cancer and EGFR-positive colorectal cancer, respectively.
• cytotoxic compounds forms an extended possibility for additionally improving cancer therapy, since these conjugates allow tumour-specific toxophore accumulation and at the same time reduce the systemic toxicity.
• clinical studies with brentuximab vedotin in Hodgkin's lymphoma and with trastuzumab-DM1 in breast cancer have yielded highly promising results, which support the development of new antibodies and new ADCs against other tumour antigens.
• the mesothelin precursor polypeptide is a glycophosphatidylinositol (GPI) anchored glycosylated cell surface protein which is cleaved proteolytically into a 30 kDa N-terminal secreted polypeptide (megakaryocyte potentiating factor, MPF) and a 40 kDa C-terminal polypeptide which is present on the cell membrane predominantly with GPI anchoring (mesothelin) (Chang, K. and I. Pastan, Proc. Natl. Acad. Sci. USA, (1996) 93(1):136).
• GPI glycophosphatidylinositol
• mesothelin represents a suitable antigen for monoclonal antibody therapy (Argani, P. et al., Clin. Cancer Res. (2001) 7(12): 3862; Hassan, R., et al., Clin. Cancer Res. (2004) 10(12 Pt 1):3937).
• the precise function of mesothelin is unknown to date; mesothelin gene-deficient mice do not exhibit any instantaneous anatomical, haematological or reproduction-restricting peculiarities (Bera, T.
• Mesothelin is a highly variable protein, which is subject to posttranslational modifications such as proteolytic digestion and glycosylations (Hassan, R., et al., Clin. Cancer Res. (2004) 10(12 Pt 1): 3937).
• Therapeutic antibodies ought therefore to recognize an invariant epitope independently of the individual mesothelin modifications.
• Antibodies can be selected according to their desired properties, such as invariant affinity or internalization, for example, with the use of monoclonal antibodies guaranteeing that these properties on the one hand apply in respect of all antibodies and on the other hand can also be produced with long-term consistency.
• Auristatin E (AE) and monomethylauristatin E (MMAE) are synthetic analogues of the dola-statins, a specific group of linear pseudopeptides which were originally isolated from marine sources and which have in some cases very potent cytotoxic activity with respect to tumour cells [for a review see e.g. G. R. Pettit, Prog. Chem. org. Nat. Prod. 70, 1-79 (1997); G. R. Pettit et al., Anti - Cancer Drug Design 10, 529-544 (1995); G. R. Pettit et al., Anti - Cancer Drug Design 13, 243-277 (1998)].
• MMAE however, possesses the disadvantage of a comparatively high systemic toxicity.
• MMAE is used more particularly in conjunction with enzymatically cleavable valine-citrulline linkers in the ADC setting for more targeted tumour therapy [WO 2005/081711-A2; S. O. Doronina et al., Bioconjugate Chem. 17, 114-124 (2006)].
• proteolytic cleavage MMAE is released preferably intracellularly from corresponding ADCs.
• MMAE is not compatible with linking units (linkers) between binder and drug that do not have an enzymatically cleavable predetermined break point [S. O. Doronina et al., Bioconjugate Chem. 17, 114-124 (2006)].
• Monomethylauristatin F is an auristatin derivative having a C-terminal phenylalanine unit which exhibits only moderate antiproliferative activity in comparison to MMAE. This fact is very probably attributable to the free carboxyl group, whose polarity and charge adversely affect the capacity of this compound to access cells.
• MMAF-OMe methyl ester of MMAF
• MMAF-OMe methyl ester of MMAF
• MMAF-OMe has been described, as a neutral-charged prodrug derivative with cell access capability, which, in comparison to MMAF, has an in vitro cytotoxicity for various carcinoma cell lines that is increased by a number of orders of magnitude [S. O. Doronina et al., Bioconjugate Chem. 17, 114-124 (2006)]. It can be assumed that this effect is brought about by MMAF itself, which, following uptake of the prodrug into the cells, is rapidly released by intracellular ester hydrolysis.
• MMAF Monomethylauristatin F
• WO 2005/081711-A2 Further auristatin analogues with a C-terminal, amidically substituted phenylalanine unit are described in WO 01/18032-A2.
• WO 02/088172-A2 and WO 2007/008603-A1 claim MMAF analogues which relate to side-chain modifications of the phenylalanine, while WO 2007/008848-A2 claims those in which the carboxyl group of the phenylalanine has been modified.
• Auristatin conjugates linked via the C-terminus have been recently described in WO 2009/117531-A1 [see also S. O. Doronina et al., Bioconjugate Chem. 19, 1960-1963 (2008)].
• auristatin derivatives such as MMAE and MMAF are also substrates for transporter proteins which are expressed by many tumour cells, and this may lead to the development of resistance to these drugs.
• ADCs binder-drug conjugates
• new N,N-dialkylauristatin derivatives with innovative, suitable linkers and binder, exhibit a very attractive activity profile, such as, for example, in terms of their specific tumour effect and/or the reduced potential of the metabolites formed intracellularly to be a substrate with respect to transporter proteins, and which are therefore suitable for the treatment and/or prophylaxis of hyperproliferative and/or angiogenic diseases, such as cancer diseases, for example.
• the present invention provides binder-drug conjugates of the general formula (Ia)
• Compounds of the invention are the compounds of the formula (Ia) and (I) and their salts, solvates and solvates of the salts, the compounds of the formulae identified below and encompassed by formula (Ia) and (I), and their salts, solvates and solvates of the salts, and also the compounds identified below as working examples and encompassed by formula (Ia) and (I), and their salts, solvates and solvates of the salts, to the extent that the compounds identified below and encompassed by formula (Ia) and (I) are not already salts, solvates and solvates of the salts.
• the compounds of the invention may exist in different stereoisomeric forms, i.e. in the form of configurational isomers or else where appropriate as conformational isomers (enantiomers and/or diastereoisomers, including those in the case of atropisomers).
• the present invention therefore encompasses the enantiomers and diastereomers and their respective mixtures.
• the stereoisomerically homogeneous constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known way; for this purpose it is preferred to use chromatographic processes, more particularly HPLC chromatography on an achiral or chiral phase.
• the present invention encompasses all of the tautomeric forms.
• the present invention also encompasses all suitable isotopic variants of the compounds of the invention.
• An isotopic variant of a compound of the invention is understood here to mean a compound in which at least one atom within the compound of the invention has been exchanged for another atom of the same atomic number but with a different atomic mass from the atomic mass which occurs commonly or predominantly in nature.
• isotopes which can be incorporated into an inventive compound are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
• isotope variants of a compound of the invention such as more particularly those in which one or more radioactive isotopes are incorporated, may be of benefit, for example, for investigating the mechanism of action or the distribution of drug in the body; owing to the comparative ease of preparation and detectability, compounds labelled with 3 H or 14 C isotopes are especially suitable for these purposes.
• isotopes such as of deuterium, for example, may lead to certain therapeutic advantages as a consequence of greater metabolic stability of the compound, such as an extension to the half-life in the body or a reduction in the active dose required, for example; such modifications of the compounds of the invention may therefore, where appropriate, also constitute a preferred embodiment of the present invention.
• Isotopic variants of the compounds of the invention can be prepared by the processes known to the skilled person, as for example in accordance with the methods described later on below and the procedures reproduced in the working examples, by using corresponding isotopic modifications of the respective reagents and/or starting compounds.
• Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds of the invention. Also encompassed are salts which although themselves not suitable for pharmaceutical applications may nevertheless be used, for example, for isolating or purifying the compounds of the invention.
• Physiologically acceptable salts of the compounds of the invention encompass acid addition salts of mineral acids, carboxylic acids and sulphonic acids, examples being salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
• Physiologically acceptable salts of the compounds of the invention also encompass salts of customary bases, such as, by way of example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropyl-amine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylpiperidine, N-methylmorpholine, arginine, lysine and 1,2-ethylenediamine.
• alkali metal salts e.g. sodium and potassium salts
• alkaline earth metal salts e.g. calcium and magnesium salts
• ammonium salts
• Solvates in the context of the invention are those forms of the compounds of the invention that form a complex in the solid or liquid state through coordination with solvent molecules. Hydrates are one specific form of solvates, in which the coordination takes place with water. Preferred solvates in the context of the present invention are hydrates.
• prodrugs of the compounds of the invention.
• the term “prodrugs” here identifies compounds which may themselves be biologically active or inactive but are converted during their residence in the body into compounds of the invention (by metabolism or hydrolysis, for example).
• (C 1 -C 4 )-Alkyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms.
• the following may be mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl and tert-butyl.
• (C 1 -C 4 )-Alkylcarbonyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms which is linked via a carbonyl group.
• Alkanediyl in the context of the invention is a linear, ⁇ , ⁇ -divalent alkyl radical having the particular number of carbon atoms indicated.
• methylene ethane-1,2-diyl (1,2-ethylene), propane-1,3-diyl (1,3-propylene), butane-1,4-diyl (1,4-butylene), pentane-1,5-diyl (1,5-pentylene), hexane-1,6-diyl (1,6-hexylene), heptane-1,7-diyl (1,7-hexylene), octane-1,8-diyl (1,8-octylene), nonane-1,9-diyl (1,9-nonylene), decane-1,10-diyl(1,10-decylene).
• (C 3 -C 7 )-Cycloalkyl and 3- to 7-membered carbocycle respectively in the context of the invention is a monocyclic, saturated cycloalkyl group having 3 to 7 carbon atoms.
• cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl may be mentioned: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• the side group of an ⁇ -amino acid in the definition of R 19 encompasses not only the side groups of the naturally occurring ⁇ -amino acids but also the side groups of homologues and isomers of these ⁇ -amino acids.
• the ⁇ -amino acid here may be in the L or D configuration or else may be present as a mixture of the L and D forms.
• Examples that may be given of side groups are as follows: methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropan-1-yl (isoleucine), butan-1-yl (norleucine), tert-butyl (2-tert-butylglycine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxy-benzyl (tyrosine), indol-3-ylmethyl (tryptophan), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 2-hydroxyethyl (homoserine), 1-hydroxyethyl (threonine), mercaptomethyl (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthio ethyl (methion
• Preferred ⁇ -amino acid side groups in the definition of R 19 are methyl (alanine), propan-2-yl (valine), 2-methylpropan-1-yl (leucine), benzyl (phenylalanine), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 1-hydroxyethyl (threonine), 4-aminobutan-1-yl (lysine), 3-aminopropan-1-yl (ornithine), 2-aminoethyl (2,4-diaminobutyric acid), aminomethyl (2,3-diaminopropionic acid), 3-guanidinopropan-1-yl (arginine).
• the L configuration is preferred in each case.
• a 4- to 7-membered heterocycle in the context of the invention is a monocyclic, saturated heterocycle having a total of 4 to 7 ring atoms, which contains one or two ring heteroatoms from the series N, O, S, SO and/or SO 2 and is linked via a ring carbon atom or optionally a ring nitrogen atom.
• Preference is given to a 5- to 7-membered heterocycle having one or two ring heteroatoms from the series N, O and/or S, more preferably a 5- or 6-membered heterocycle having one or two ring heteroatoms from the series N and/or O.
• azetidinyl oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl and hexahydro-1,4-diazepinyl.
• linker is understood in the broadest sense as a chemical unit which comprises a covalent bond or a series of atoms that links a binder covalently to a drug.
• linker is understood preferably as a series of atoms in the sense of the present invention that links a binder covalently to a drug.
• linkers may be represented, for example, by divalent chemical units, such as alkyldiyls, aryldiyls, heteroaryldiyls, heterocyclyldiyls, dicarbonyl acid esters, dicarbonyl acid amides.
• binding is understood in the broadest sense as a molecule which binds to a target molecule which is present on a particular target cell population to be addressed with the binder-drug conjugate.
• the term “binder” should be understood in its broadest interpretation and encompasses, for example, lectins, proteins which are able to bind particular sugar chains, or phospholipid-binding proteins.
• Such binders comprise, for example, high molecular mass proteins (binding proteins), polypeptides or peptides (binding peptides), non-peptidic (e.g. aptamers (U.S. Pat. No. 5,270,163) review article by Keefe A D., et al., Nat. Rev. Drug Discov.
• Binding proteins are, for example, antibodies and antibody fragments or antibody mimetics such as, for example, affibodies, adnectins, anticalins, DARPins, avimers, nanobodies (review articles by Gebauer M. et al., Curr. Opinion in Chem. Biol. 2009; 13:245-255; Nuttall S. D. et al., Curr. Opinion in Pharmacology 2008; 8:608-617).
• Binding peptides are, for example, ligands of a ligand-receptor pair, such as VEGF in the ligand-receptor pair VEGF/KDR, such as transferrin of the ligand-receptor pair transferrin/transferrin receptor, or cytokines/cytokine receptor, such as TNFalpha in the ligand receptor pair TNFalpha/TNFalpha receptor.
• ligands of a ligand-receptor pair such as VEGF in the ligand-receptor pair VEGF/KDR
• transferrin of the ligand-receptor pair transferrin/transferrin receptor such as transferrin of the ligand-receptor pair transferrin/transferrin receptor
• cytokines/cytokine receptor such as TNFalpha in the ligand receptor pair TNFalpha/TNFalpha receptor.
• Preferred binders in accordance with the invention are (more particularly human, monoclonal) antibodies or antigen-binding antibody fragments which bind to mesothelin.
• n in other words the number of toxophore molecules per antibody molecule, is preferably in the range from 1 to 10, more preferably 2 to 8.
• a “target molecule” is understood in the broadest sense to be a molecule which is present in the target cell population, and may be a protein (e.g. a receptor of a growth factor) or a non-peptidic molecule (e.g. a sugar or phospholipid). Preferably it is a receptor or an antigen.
• extracellular target molecule describes a target molecule which is attached to the cell and which is located on the outside of a cell or the part of a target molecule which is located on the outside of a cell, i.e. a binder may bind to an intact cell at its extracellular target molecule.
• An extracellular target molecule may be anchored in the cell membrane or may be part of the cell membrane.
• the skilled person knows of methods for identifying extracellular target molecules. For proteins this may be done via determination of the transmembrane domain(s) and the orientation of the protein in the membrane. This data is generally recorded in protein databases (e.g. SwissProt).
• cancer target molecule describes a target molecule which is multiply present on one or more cancer cell types in comparison to non-cancer cells of the same tissue type.
• the cancer target molecule is preferably present selectively on one or more cancer cell types in comparison to non-cancer cells of the same tissue type, with “selectively” describing an at least twofold accumulation on cancer cells in comparison to non-cancer cells of the same tissue type (a “selective cancer target molecule”).
• selective cancer target molecule allows selective therapy of cancer cells with the conjugates of the invention.
• the binder may be linked via a bond to the linker.
• the linking of the binder may take place by means of a heteroatom of the binder.
• Inventive heteroatoms of the binder that may be used for linking are sulphur (in one embodiment via a sulphhydryl group of the binder), oxygen (in accordance with the invention by means of a carboxyl or hydroxy group of the binder) and nitrogen (in one embodiment via a primary or secondary amine group or amide group of the binder).
• Preferred in accordance with the invention is the conjugation of the toxophores to the antibody via one or more sulphur atoms of cysteine residues of the antibody and/or via one or more NH groups of lysine residues of the antibody. These heteroatoms may be present in the natural binder or may be introduced by means of methods of chemistry or molecular biology.
• the linking of the binder to the toxophore has little influence over the binding activity of the binder to the target molecule. In a preferred embodiment the linking has no influence on the binding activity of the binder to the target molecule.
• an immunoglobulin molecule preferably comprises a molecule having four polypeptide chains, two heavy chains (H chains) and two light chains (L chains), which are linked typically by disulphide bridges.
• Each heavy chain comprises a variable domain of the heavy chain (abbreviated to VH) and a constant domain of the heavy chain.
• the constant domain of the heavy chain may encompass, for example, three domains CH1, CH2 and CH3.
• Each light chain comprises a variable domain (abbreviated to VL) and a constant domain.
• the constant domain of the light chain comprises one domain (abbreviated to CL).
• CL constant domain
• the VH and VL domains may be further subdivided into regions having hypervariability, also called complementarity-determining regions (abbreviated to CDR), and regions having a low sequence variability (“framework region”, abbreviated to FR).
• CDR complementarity-determining regions
• FR low sequence variability
• Each VH and VL region is typically composed of three CDRs and up to four FRs. For example, in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
• An antibody may be obtained from any species suitable for the antibody, such as, for example, rabbit, lama, camel, mouse or rat. In one embodiment the antibody is of human or murine origin.
• An antibody may for example be human, humanized or chimeric.
• the term “monoclonal” antibody identifies antibodies which have been obtained from a population of substantially homogeneous antibodies, i.e. individual antibodies of the population are identical except for naturally occurring mutations which may occur in small numbers. Monoclonal antibodies recognize a single antigenic binding site with a high specificity. The term “monoclonal antibody” does not refer to a particular production method.
• the term “intact” antibody refers to antibodies which comprise not only an antigen-binding domain but also the constant domain of the light and heavy chain.
• the constant domain may be a naturally occurring domain, or a variant thereof in which a plurality of amino acid positions have been altered.
• modified intact antibody refers to intact antibodies which have been fused with another polypeptide or protein, not originating from an antibody, via the amino terminus or carboxyl terminus thereof, by means of a covalent bond (e.g. a peptide linkage).
• antibodies may be modified by introducing reactive cysteines at defined locations, in order to facilitate coupling to a toxophore (see Junutula et al. Nat. Biotechnol. 2008 August; 26(8):925-32).
• human antibody identifies antibodies which can be obtained from a human being or are synthetic human antibodies.
• a “synthetic” human antibody is an antibody which in parts or as a whole is obtainable from synthetic sequences in silico which are based on the analysis of human antibody sequences.
• a human antibody may be encoded, for example, by a nucleic acid which has been isolated from a library of antibody sequences which are of human origin.
• One example of such antibodies can be found in Soderlind et al., Nature Biotech. 2000, 18:853-856.
• humanized or “chimeric” antibody describes antibodies which consist of a non-human and of a human sequence component. In these antibodies, part of the sequences of the human immunoglobulin (recipient) is replaced by sequence components of a non-human immunoglobulin (donor). In many cases the donor is a murine immunoglobulin. With humanized antibodies, amino acids of the CDR in the recipient are replaced by amino acids of the donor. In some cases, amino acids of the framework as well are replaced by corresponding amino acids of the donor. In some cases the humanized antibody contains amino acids which were present neither in the recipient nor in the donor and which were inserted during the optimization of the antibody. In the case of chimeric antibodies, the variable domains of the donor immunoglobulin are fused with the constant regions of a human antibody.
• complementarity-determining region refers to those amino acids in a variable antibody domain that are necessary for binding to the antigen. Every variable region typically has three CDR regions, identified as CDR1, CDR2 and CDR3. Each CDR region may comprise amino acids according to the definition of Kabat and/or amino acids of a hypervariable loop, defined according to Chotia.
• the definition according to Kabat encompasses, for example, the region of approximately amino acid position 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) of the variable light chain and 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) of the variable heavy chain (Kabat et al., Sequences of Proteins of Immulological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).
• Chotia encompasses, for example, the region of approximately amino acid position 26-32 (CDR1), 50-52 (CDR2) and 91-96 (CDR3) of the variable light chain and 26-32 (CDR1), 53-55 (CDR2) and 96-101 (CDR3) of the variable heavy chain Chothia and Lesk; J Mol Biol 196: 901-917 (1987)).
• CDR may comprise amino acids from one CDR region as defined by Kabat and Chotia.
• antibodies may be divided into different classes. There are five main classes of intact antibodies: IgA, IgD, IgE, IgG and IgM, and a number of them may be broken down into further subclasses (isotypes), e.g. IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2.
• the constant domains of the heavy chain that correspond to the different classes are identified as [alpha/ ⁇ ], [delta/ ⁇ ], [epsilon/ ⁇ ], [gamma/ ⁇ ] and [mu/ ⁇ ]. Both the three-dimensional structure and the subunit structure of antibodies are known.
• the term “functional fragment” or “antigen-binding antibody fragments” of a antibody/immunoglobulin is defined as a fragment of an antibody/immunoglobulin (e.g. the variable domains of an IgG) which further encompasses the antigen binding domains of the antibody/immunoglobulin.
• the “antigen binding domain” of an antibody typically encompasses one or more hypervariable regions of an antibody, e.g. the CDR, CDR2 and/or CDR3 region.
• the “framework” or “scaffold” region of an antibody may also play a part with regard to the binding of the antibody to the antigen.
• the framework region forms the scaffold for the CDRs.
• the antigen-binding domain preferably encompasses at least amino acids 4 to 103 of the variable light chain and amino acid 5 to 109 of the variable heavy chain, more preferably amino acid 3 to 107 of the variable light chain and 4 to 111 of the variable heavy chain, particular preference being given to the complete variable light and heavy chains, i.e. amino acid 1-109 of the VL and 1 to 113 of the VH (numbering according to WO97/08320).
• “Functional fragments” or “antigen-binding antibody fragments” of the invention encompass, non-conclusively, Fab, Fab′, F(ab′) 2 and Fv fragments, diabodies, Single Domain Antibodies (DAbs), linear antibodies, individual chains of antibodies (single-chain Fv, abbreviated to ScFv); and multispecific antibodies, such as bi and tri-specific antibodies, for example, formed from antibody fragments C. A. K Borrebaeck, editor (1995) Antibody Engineering (Breakthroughs in Molecular Biology), Oxford University Press; R. Kontermann & S. Duebel, editors (2001) Antibody Engineering (Springer Laboratory Manual), Springer Verlag).
• Multispecific antibodies are those having identical binding sites.
• Multispecific antibodies may be specific for different epitopes of an antigen or may be specific for epitopes of more than one antigen (see, for example WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., 1991, J. Immunol. 147:60 69; U.S. Pat. Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; or Kostelny et al., 1992, J. Immunol. 148: 1547 1553).
• An F(ab′) 2 or Fab molecule may be constructed such that the number of intermolecular disulphide interactions occurring between the Ch1 and the CL domains can be reduced or else completely prevented.
• “Functional fragments” or “antigen-binding antibody fragments” may be fused with another polypeptide or protein, not originating from an antibody, via the amino terminus or carboxyl terminus thereof, by means of a covalent bond (e.g. a peptide linkage). Furthermore, antibodies and antigen-binding fragments may be modified by introducing reactive cysteines at defined locations, in order to facilitate coupling to a toxophore (see Junutula et al. Nat. Biotechnol. 2008 August; 26(8):925-32).
• Polyclonal antibodies can be prepared by methods known to a person of ordinary skill in the art.
• Monoclonal antibodies may be prepared by methods known to a person of ordinary skill in the art (Köhler and Milstein, Nature, 256, 495-497, 1975).
• Human and humanized monoclonal antibodies may be prepared by methods known to a person of ordinary skill in the art (Olsson et al., Meth Enzymol. 92, 3-16 or Cabilly et al U.S. Pat. No. 4,816,567 or Boss et al U.S. Pat. No. 4,816,397).
• Antibodies of the invention may be obtained from recombinant antibody libraries consisting for example of the amino acid sequences of a multiplicity of antibodies compiled from a large number of healthy volunteers. Antibodies may also be produced by means of known recombinant DNA technologies. The nucleic acid sequence of an antibody can be obtained by routine sequencing or is available from publically accessible databases.
• an “isolated” antibody or binder has been purified to remove other constituents of the cell. Contaminating constituents of a cell which may interfere with a diagnostic or therapeutic use are, for example, enzymes, hormones, or other peptidic or non-peptidic constituents of the cell.
• a preferred antibody or binder is one which has been purified to an extent of more than 95%, relative to the antibody or binder (determined for example by Lowry method, UV-Vis spectroscopy or by SDS capillary gel electrophoresis).
• an antibody is normally prepared by one or more purification steps.
• specific binding refers to an antibody or binder which binds to a predetermined antigen/target molecule.
• Specific binding of an antibody or binder typically describes an antibody or binder having an affinity of at least 10 ⁇ 7 M (as Kd value; i.e. preferably those with smaller Kd values than 10 ⁇ 7 M), with the antibody or binder having an at least two times higher affinity for the predetermined antigen/target molecule than for a non-specific antigen/target molecule (e.g. bovine serum albumin, or casein) which is not the predetermined antigen/target molecule or a closely related antigen/target molecule.
• Kd value i.e. preferably those with smaller Kd values than 10 ⁇ 7 M
• Antibodies which are specific against a cancer cell antigen can be prepared by a person of ordinary skill in the art by means of methods with which he or she is familiar (such as recombinant expression, for example) or may be acquired commercially (as for example from Merck KGaA, Germany).
• Examples of known commercially available antibodies in cancer therapy are Erbitux® (cetuximab, Merck KGaA), Avastin® (bevacizumab, Roche) and Herceptin® (trastuzumab, Genentech).
• the antibody is produced recombinantly in CHO cells.
• the compounds of the formula (I) represent a subgroup of the compounds of the formula (Ia).
• a preferred subject of the invention are binder-drug conjugates of the general formula (Ia) in which
• Q 1 is a 4- to 7-membered heterocycle
• Preferred subject of the invention are binder-drug conjugates of the general formula (Ia) in which
• Preferred subject matter of the invention are binder-drug conjugates of the general formula (Ia) in which
• Preferred subject matter of the invention are binder-drug conjugates of the general formula (Ia), in which
• Preferred subject matter of the invention are binder-drug conjugates of the general formula (Ia) in which
• Preferred subject matter of the present invention are binder-drug conjugates of the general formula (Ia) as indicated above, in which
• Preferred subject matter of the invention are binder-drug conjugates of the general formula (Ia), in which
• Preferred subject matter of the present invention are binder-drug conjugates of the general formula (Ia) as indicated above, in which
• Preferred subject matter of the invention are binder-drug conjugates of the general formula (Ia), in which
• the present invention additionally provides compounds of the formula (XXXI)
• the present invention additionally provides binder-drug conjugates of the general formula (I)
• Preferred subject matter of the invention are binder-drug conjugates of the general formula (I), in which
• Preferred subject matter of the invention are binder-drug conjugates of the general formula (I),
• Preferred subject matter of the present invention are binder-drug conjugates of the general formula (I), in which
• the present invention additionally provides compounds of the formula (XXX)
• L 1 is a bond, linear (C 1 -C 10 )-alkanediyl or is a group of the formula
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred in the context of the present invention are also compounds of the formula (Ia), (XXXa) and (XXXI), in which
• Preferred subject matter of the invention are binder-drug conjugates of the general formula (Ia), in which
• drug-binder conjugates selected from the following compounds:
• binder-drug conjugates selected from the following compounds:
• radicals that are indicated individually in the respective combinations and preferred combinations of radicals are also replaced arbitrarily by radical definitions of other combinations, independently of the respective combinations of radicals that are indicated.
• the partial reduction of the antibody and also the subsequent conjugation of the (partially) reduced antibody with a compound of the formula (II) or (IIa) takes place in accordance with the methods known to the skilled person, see e.g. Ducry et. al., Bioconj. Chem. 2010, 21, 5 and references herein, Klussman et. al., Bioconj. Chem. 2004, 15(4), 765-773.
• the mild reduction of the antibody is accomplished preferably by addition of 2-6 equivalents of TCEP to the antibody, which is present in a suitable buffer solution, preferably phosphate buffer, and by stirring for 30-180 minutes at temperatures between 15 and 40° C., preferably at RT.
• D and L 2 each have the definitions indicated above.
• D, L 1 and L 2 each have the definitions indicated above.
• R 25 and PG 1 each have the definitions indicated above and PG 2 is a suitable carboxyl-protective group, more particularly benzyl, to give a compound (XII-A) or (XII-B)
• the compounds of the formula (III), in which L 1 and B are a bond can be prepared by reacting a compound of the formula (IX) in an inert solvent in the presence of a suitable coupling reagent and a suitable base with N-hydroxysuccinimide to give a compound of the formula (III-A)
• D and L 2 each have the definitions indicated above.
• D, P, Q 2A and L 2 each have the definitions indicated above.
• L 1A is linear (C 1 -C 10 )-alkanediyl or is a group of the formula
• Such solvents include, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl)ether, or other solvents such as dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide or else water. It is also possible to use mixtures of these solvents. As solvent it is preferred to use a 1,4-dioxane/water mixture, with addition of acetic acid or dilute hydrochloric acid as catalyst.
• alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol
• ethers such as tetrahydrofuran, 1,4-dioxan
• Reducing agents suitable for this reaction are, in particular, complex borohydrides, such as, for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, tetra-n-butylammonium borohydride or borane-pyridine complex. It is preferred to use sodium cyanoborohydride or borane-pyridine complex.
• complex borohydrides such as, for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, tetra-n-butylammonium borohydride or borane-pyridine complex. It is preferred to use sodium cyanoborohydride or borane-pyridine complex.
• the reactions (IV)+(V) ⁇ (VI) and (IV)+(VIII) ⁇ (IX) take place in general in a temperature range from 0° C. to +120° C., preferably at +50° C. to +100° C.
• the reactions may be carried out under atmospheric, increased or reduced pressure (e.g. from 0.5 to 5 bar); it is usual to operate at atmospheric pressure.
• inert solvents for these coupling reactions are ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl)ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or dipolar-aprotic solvents such as acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, pyridine, dimethyl sulphoxide (DMSO), N,N-
• activating/condensing agents for these couplings include carbodiimides such as N,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N,N′-carbonyldiimidazole (CDI) or isobutyl chloroformate, 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, phosphorus compounds such as propanephosphonic anhydride,
• tertiary amine bases such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine, pyridine or 4-N,N-dimethylaminopyridine.
• N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride EDC
• HOBt 1-hydroxybenzotriazole
• HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
• the coupling reactions (IX)+(X) ⁇ (II-C), (XII-A) or (XII-B)+(X) ⁇ (II-D-A) or (II-D-B), (IX)+(XIII) ⁇ (XIV), (IX)+(XV) ⁇ (XVI) and (XXII)+(XXIII) ⁇ (II-D) are carried out in general in a temperature range from ⁇ 20° C. to +60° C., preferably at 0° C. to +40° C.
• the reactions may take place under atmospheric, at increased or at reduced pressure (e.g. from 0.5 to 5 bar); it is usual to operate under atmospheric pressure.
• esterifications (IX)+(XVIII) ⁇ (XII) and (IX)+(XI-A) or (XI-B) ⁇ (XII-A) or (XII-B), (IX)+(XXIV) ⁇ (XXV) and also (IX)+(XXI) ⁇ (XXII) take place in analogy to the above-described amide coupling reactions. These reactions take place preferably in dichloromethane, using N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine at a temperature of +50° C. to 100° C. under atmospheric pressure.
• EDC N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride
• 4-dimethylaminopyridine at a temperature of +50° C. to 100° C. under atmospheric pressure.
• such protective groups are introduced and removed in accordance with customary methods known from peptide chemistry [see, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in organic Synthesis , Wiley, New York, 1999; M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis , Springer-Verlag, Berlin, 1984].
• two or more protected groups are present, they can be liberated again optionally simultaneously in a one-pot reaction, or else liberated again in separate reaction steps.
• tert-butoxycarbonyl Boc
• benzyloxycarbonyl Z
• (9H-fluoren-9-ylmethoxy)carbonyl Fmoc
• tert-butyl or benzyl for a hydroxyl or carboxyl function it is preferred to use tert-butyl or benzyl as protective group PG 2 .
• tert-butyl or tert-butoxycarbonyl group is typically accomplished by treatment with a strong acid, such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid, in an inert solvent such as diethyl ether, 1,4-dioxane, dichloromethane or acetic acid; this reaction may optionally also be carried out without addition of an inert solvent.
• a strong acid such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid
• an inert solvent such as diethyl ether, 1,4-dioxane, dichloromethane or acetic acid
• this group is removed preferably by hydrogenolysis in the presence of a suitable palladium catalyst, such as palladium on activated carbon, for example.
• a suitable palladium catalyst such as palladium on activated carbon, for example.
• the (9H-fluoren-9-ylmethoxy)carbonyl group is generally eliminated using a secondary amine base such as
• the reaction (VI) ⁇ (II-A) takes place in a solvent which is inert under the reaction conditions, such as, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl)ether, alcohols such as methanol, ethanol, isopropanol, n-butanol or tert-butanol, or dipolar-aprotic solvents such as acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, pyridine, dimethyl sulphoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N,N′-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP) or water.
• a solvent which is inert under the reaction conditions
• ethers such as
• Suitable bases for the reaction (VI) ⁇ (II-A) are, for example, alkali metal carbonates such as potassium carbonate, sodium carbonate or lithium carbonate, alkali metal hydrogencarbonates such as sodium or potassium hydrogencarbonate or alkali metal alkoxides such as sodium methoxide, sodium ethoxide or potassium tert-butoxide. It is preferred to use sodium hydrogencarbonate.
• the reaction (VI) ⁇ (II-A) takes place in a temperature range from 0° C. to +50° C., preferably at +10° C. to +30° C.
• the reaction may take place under atmospheric, under elevated or under reduced pressure (e.g. from 0.5 to 5 bar); it is usual to operate under atmospheric pressure.
• the reaction (VI)+(VII) ⁇ (II-B) takes place in a solvent which is inert under the reaction conditions, such as, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl)ether, alcohols such as methanol, ethanol, isopropanol, n-butanol or tert-butanol, or dipolar-aprotic solvents such as acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, pyridine, dimethyl sulphoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N,N′-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP) or water. It is also possible to use mixtures of such solvents. Preference is
• Suitable bases for the reaction (VI)+(VII) ⁇ (II-B) are, for example, tertiary amine bases such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine, pyridine or 4-N,N-dimethylaminopyridine. Preference is given to using N,N-diisopropylethylamine.
• the reaction (VI)+(VII) ⁇ (II-B) takes place in a temperature range from 0° C. to +50° C., preferably at +10° C. to +30° C.
• the reaction may take place under atmospheric, under elevated or under reduced pressure (e.g. from 0.5 to 5 bar); it is usual to operate under atmospheric pressure.
• Suitable solvents are ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis(2-methoxyethyl)ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or dipolar-aprotic solvents such as acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, pyridine, dimethyl sulphoxide (DMSO), N,N-dimethylformamide (DM
• Suitable bases for these reactions are, for example, tertiary amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine, pyridine or 4-N,N-dimethylaminopyridine. Preference is given to using N,N-diisopropylethylamine, optionally with addition of 4-N,N-dimethylaminopyridine.
• the reactions (IX) ⁇ (III-A), (XIV) ⁇ (III-B) and (XVI) ⁇ (III-C) and also (VI)+(XVII) ⁇ (III-D) and (XIX)+(XX) ⁇ (III-E) take place in a temperature range from 0° C. to +50° C., preferably at +10° C. to +30° C.
• the reaction may take place under atmospheric, under elevated or under reduced pressure (e.g. from 0.5 to 5 bar); it is usual to operate under atmospheric pressure.
• the compounds of the formulae (II), (III), (I-A) and (I-B) are sub-quantities of the compounds of the formulae (IIa), (IIIa), (Ia-A) and (Ia-B), respectively, where R 35 is methyl.
• the preparation of the compounds (IIa) and (IIIa) takes place in analogy to the preparation of the compound of the formulae (II) and (III) as described above.
• the compounds of the formula (IV) can be prepared from commercially available amino acid building blocks or those known from the literature (see, for example, Pettit et al., Synthesis 1996, 719; Shioiri et al., Tetrahedron Lett. 1991, 32, 931; Shioiri et al., Tetrahedron 1993, 49, 1913; Koga et al., Tetrahedron Lett. 1991, 32, 2395; Vidal et al., Tetrahedron 2004, 60, 9715; Poncet et al., Tetrahedron 1994, 50, 5345. Pettit et al., J. org. Chem. 1994, 59, 1796) in analogy to processes known from the literature, in accordance with customary methods of peptide chemistry, and as described in the present experimental section.
• the synthesis schemes below illustrate the preparation by way of example.
• ADCs may be prepared by way of example in accordance with the following methods:
• the binder binds to a target molecule which is present on a cancer cell. In one preferred embodiment the binder binds to a cancer target molecule.
• the target molecule is a selective cancer target molecule.
• the target molecule is a protein.
• the target molecule is an extracellular target molecule.
• the extracellular target molecule is a protein.
• Cancer target molecules are known to the skilled person. Examples thereof are listed below.
• cancer target molecules are as follows:
• EGF receptor NCBI reference sequence NP — 005219.2
• epidermal growth factor receptor isoform a precursor [ Homo sapiens ] MRPSGTAGAALLALLAALCPASRA LEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFN NCEVVLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYE NSYALAVLSNYDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSD FLSNMSMDFQNHLGSCQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKS PSDCCHNQCAAGCTGPRESDCLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEG KYSFGATCVKKCPRNYVVTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCN GIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTP
• the extracellular domain is marked by underlining.
• Mesothelin is encoded by amino acids 296-598. Amino acids 37-286 code for “megakaryocyte-potentiating factor”. Mesothelin is anchored in the cell membrane by a GPI anchor and is localized extracellularly.
• the extracellular domain is marked by underlining.
• the matured, extracellular domain is marked by underlining (SEQ ID NO:1).
• CD52 NCBI reference sequence NP — 001794.2
• B-lymphocyte antigen CD20 [ Homo sapiens ] MTTPRNSVNGTFPAEPMKGPIAMQSGPKPLFRRMSSLVGPTQSFFMRESKTLGAVQI MNGLFHIALGGLLMIPAGIYAPICVTVWYPLWGGIMYIISGSLLAATEKNSRKCLVKG KMIMNSLSLFAAISGMILSIMDILNIKISHFLKMESLNFIRAHTPYINIYNCEPANPSEKN SPSTQYCYSIQSLFLGILSVMLIFAFFQELVIAGIVENEWKRTCSRPKSNIVLLSAEEKK EQTIEIKEEVVGLTETSSQPKNEEDIEIIPIQEEEEEETETNFPEPPQDQESSPIENDSSP (8) The lymphocyte-activating antigen CD30 (SwissProt ID P28908)
• tumor necrosis factor receptor superfamily member 8 isoform 1 precursor [ Homo sapiens ] MRVLLAALGLLFLGALRAFPQDRPFEDTCHGNPSHYYDKAVRRCCYRCPMGLFPTQ QCPQRPTDCRKQCEPDYYLDEADRCTACVTCSRDDLVEKTPCAWNSSRVCECRPGM FCSTSAVNSCARCFFHSVCPAGMIVKFPGTAQKNTVCEPASPGVSPACASPENCKEPS SGTIPQAKPTPVSPATSSASTMPVRGGTRLAQEAASKLTRAPDSPSSVGRPSSDPGLSP TQPCPEGSGDCRKQCEPDYYLDEAGRCTACVSCSRDDLVEKTPCAWNSSRTCECRP GMICATSATNSRARCVPYPICAAETVTKPQDMAEKDTTFEAPPLGTQPDCNPTPENG EAPASTSPTQSLLVDSQASKTLPIPTSAPVALSSTGKPVLDAGPVLFWVILVLVLVLVLV
• B-cell receptor CD22 isoform 1 precursor [ Homo sapiens ] MHLLGPWLLLLVLEYLAFSDSSKWVFEHPETLYAWEGACVWIPCTYRALDGDLESFI LFHNPEYNKNTSKFDGTRLYESTKDGKVPSEQKRVQFLGDKNKNCTLSIHPVHLNDS GQLGLRMESKTEKWMERIHLNVSERPFPPHIQLPPEIQESQEVTLTCLLNFSCYGYPIQ LQWLLEGVPMRQAAVTSTSLTIKSVFTRSELKFSPQWSHHGKIVTCQLQDADGKFLS NDTVQLNVKHTPKLEIKVTPSDAIVREGDSVTMTCEVSSSNPEYTTVSWLKDGTSLK KQNTFTLNLREVTKDQSGKYCCQVSNDVGPGRSEEVFLQVQYAPEPSTVQILHSPAV EGSQVEFLCMSLANPLPTNYTW
• B-lymphocyte antigen CD19 isoform 1 precursor [ Homo sapiens ] MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPL KPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNV EGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPP CLPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLEL KDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWL LRTGGWKVSAVTLAYLIFCLCSLVGILHLQRALVLRRKRKRMTDPTRRFFKVTPPPG SGPQNQYGNVLSLPTPTSGLGRAQRWAAGLGGTAPSY
• mucin-1 isoform 1 precursor [ Homo sapiens ] MTPGTQSPFFLLLLLTVLTVVTGSGHASSTPGGEKETSATQRSSVPSSTEKNALSTGVS FFFLSFHISNLQFNSSLEDPSTDYYQELQRDISEMFLQIYKQGGFLGLSNIKFRPGSVVV QLTLAFREGTINVHDVETQFNQYKTEAASRYNLTISDVSVSDVPFPFSAQSGAGVPG WGIALLVLVCVLVALAIVYLIALAVCQCRRKNYGQLDIFPARDTYHPMSEYPTYHTH GRYVPPSSTDRSPYEKVSAGNGGSSLSYTNPAVAATSANL (17) The surface protein CD138 (SwissProt ID P18827)
• teratocarcinoma-derived growth factor 1 isoform 1 precursor [ Homo sapiens ] MDCRKMARFSYSVIWIMAISKVFELGLVAGLGHQEFARPSRGYLAFRDDSIWPQEEP AIRPRSSQRVPPMGIQHSKELNRTCCLNGGTCMLGSFCACPPSFYGRNCEHDVRKEN CGSVPHDTWLPKKCSLCKCWHGQLRCFPQAFLPGCDGLVMDEHLVASRTPELPPSA RTTTFMLVGICLSIQSYY (20) The prostate-specific membrane antigen PSMA (Swiss Prot ID: Q04609)
• the cancer target molecule is selected from the group consisting of the cancer target molecules (1)-(51).
• the binder binds to an extracellular cancer target molecule which is selected from the group consisting of the cancer target molecules (1)-(51).
• the binder binds specifically to an extracellular cancer target molecule which is selected from the group consisting of the cancer target molecules (1)-(51).
• the cancer target molecule is selected from the group consisting of EGF receptor (NP — 005219.2), mesothelin (Q 13421 -3), C4.4a (NP — 055215.2) and carboanhydrase IX (CA IX; NP — 001207.2).
• the binder binds to an extracellular cancer target molecule which is selected from the group consisting of EGF receptor (NP — 005219.2), mesothelin (Q 13421 -3), C4.4a (NP — 055215.2) and carboanhydrase IX (CA IX; Q 16790 ).
• the binder binds specifically to an extracellular cancer target molecule which is selected from the group consisting of EGF receptor (NP — 005219.2), mesothelin (Q 13421 -3), C4.4a (NP — 055215.2) and carboanhydrase IX (CA IX; Q 16790 ).
• EGF receptor NP — 005219.2
• mesothelin Q 13421 -3
• C4.4a NP — 055215.2
• CA IX carboanhydrase IX
• the binder after binding to its extracellular target molecule on the target cell, is internalized by the target cell as a result of the binding.
• the binder-drug conjugate which may be an immunoconjugate or an ADC, is taken up by the target cell.
• the binder is a binding protein. In one preferred embodiment the binder is an antibody, an antigen-binding antibody fragment, a multispecific antibody or an antibody mimetic.
• Preferred antibody mimetics are affibodies, adnectins, anticalins, DARPins, avimers, or nanobodies.
• Preferred multispecific antibodies are bispecific and trispecific antibodies.
• the binder is an antibody or an antigen-binding antibody fragment, more preferably an isolated antibody or an isolated antigen-binding antibody fragment.
• Preferred antigen-binding antibody fragments are Fab, Fab′, F(ab′) 2 and Fv fragments, diabodies, DAbs, linear antibodies and scFv. Particularly preferred are Fab, diabodies and scFv.
• the binder is an antibody.
• Particularly preferred are monoclonal antibodies or antigen-binding antibody fragments thereof.
• Further particularly preferred are human, humanized or chimeric antibodies or antigen-binding antibody fragments thereof.
• Antibodies or antigen-binding antibody fragments which bind cancer target molecules may be prepared by a person of ordinary skill in the art using known processes, such as, for example, chemical synthesis or recombinant expression. Binders for cancer target molecules may be acquired commercially or may be prepared by a person of ordinary skill in the art using known processes, such as, for example, chemical synthesis or recombinant expression. Further processes for preparing antibodies or antigen-binding antibody fragments are described in WO 2007/070538 (see page 22 “Antibodies”). The skilled person knows how processes such as phage display libraries (e.g.
• Morphosys HuCAL Gold can be compiled and used for discovering antibodies or antigen-binding antibody fragments (see WO 2007/070538, page 24 ff and Example 1 on page 70, Example 2 on page 72). Further processes for preparing antibodies that use DNA libraries from B-cells are described for example on page 26 (WO 2007/070538). Processes for humanizing antibodies are described on page 30-32 of WO2007070538 and in detail in Queen, et al., Pros. Natl. Acad. Sci. USA 86:10029-10033, 1989 or in WO 90/0786.
• Processes for preparing an IgG1 antibody are described for example in WO 2007/070538 in Example 6 on page 74 ff. Processes which allow the determination of the internalization of an antibody after binding to its antigen are known to the skilled person and are described for example in WO 2007/070538 on page 80. The skilled person is able to use the processes described in WO 2007/070538 that have been used for preparing carboanhydrase IX (Mn) antibodies in analogy for the preparation of antibodies with different target molecule specificity.
• cetuximab examples of antibodies which bind the cancer target molecules EGFR are cetuximab (INN number 7906), panitumumab (INN number 8499) and nimotuzumab (INN number 8545).
• Cetuximab Drug Bank Accession Number DB00002
• DB00002 Drug Bank Accession Number DB00002
• Cetuximab is indicated for the treatment of metastasizing, EGFR expressing, colorectal carcinoma with wild type K-Ras gene. It has an affinity of 10 ⁇ 10 M
• Panitumumab (INN number 8499) (Drug Bank Accession Number DB01269) is a recombinant monoclonal human IgG2 antibody which binds specifically to the human EGF receptor 1 and is sold by Abgenix/Amgen. Panitumumab originates from the immunization of transgenic mice (XenoMouse). These mice are capable of producing human immunoglobulin (light and heavy chains). A specific B-cell clone was selected which produces antibodies against EGFR, and this clone was immortalized with CHO cells (Chinese hamster ovary cells). These cells are now used for the production of a 100% human antibody.
• Panitumumab is indicated for the treatment of EGFR-expressing, metastasizing colorectal carcinoma, which is resistant to chemotherapeutic treatment with fluoropyrimidine, oxaliplatin and irinotecan. It has an affinity of 10 ⁇ 11 M.
• Nimotuzumab (INN number 8545) (EP 00586002, EP 00712863) is a humanized monoclonal IgG1 antibody which binds specifically to the human EGF receptor 1 and is sold by YM BioScienecs Inc. (Mississauga Canada). It is produced in non-secreting NSO cells (mammalian cell line). Nimotuzumab is approved for the treatment of head-and-neck tumours, highly malignant astrocytoma and glioblastoma multiforms (not in EU and US) and pancreatic carcinoma (orphan drug, EMA). It has an affinity of 10 ⁇ 8 M.
• the anti-EGFR antibodies are selected from the group consisting of cetuximab, panitumumab, nimotuzumab, zalutumumab, necitumumab, matuzumab, RG-716, GT-MAB 5.2-GEX, ISU-101, ABT-806, SYM-004, MR1-1, SC-100, MDX-447, and DXL-1218.
• the anti-EGFR antibodies are selected from the group consisting of cetuximab, panitumumab, nimotuzumab, zalutumumab, necitumumab and matuzumab.
• the anti-EGFR antibodies or antigen-binding antibody fragments are selected from the group consisting of
• antibodies or antigen-binding antibody fragments comprising the three CDR regions of the light chain and the three CDR regions of the heavy chain of one of the following antibodies: cetuximab, panitumumab, nimotuzumab, zalutumumab, necitumumab, matuzumab, RG-716, GT-MAB 5.2-GEX, ISU-101, ABT-806, SYM-004, MR1-1, SC-100, MDX-447, and DXL-1218.
• antibodies or antigen-binding antibody fragments comprising the three CDR regions of the light chain and the three CDR regions of the heavy chain of one of the following antibodies: cetuximab, panitumumab, nimotuzumab, zalutumumab, necitumumab, matuzumab.
• the anti-carboanhydrase IX antibodies or antigen-binding antibody fragments are selected from the group consisting of anti-carboanhydrase IX antibodies or antigen-binding antibody fragments 3ee9 (Claim 4 (a) in WO 2007/070538-A2), 3ef2 (Claim 4 (b) in WO2007/070538-A2), 1e4 (Claim 4 (c) in WO 2007/070538-A2), 3a4 (Claim 4 (d) in WO 2007/070538-A2), 3ab4 (Claim 4 (e) in WO 2007/070538-A2), 3ah10 (Claim 4 (f) in WO 2007/070538-A2), 3bb2 (Claim 4 (g) in WO 2007/070538-A2), 1aa1 (Claim 4 (h) in WO 2007/070538-A2), 5a6 (Claim 4 (a)
• anti-carboanhydrase IX antibodies or antigen-binding antibody fragments thereof which comprise the sequences of the three CDR regions of the light chain and the sequences of the three CDR regions of the heavy chain of the antibody 3ee9 (from WO 2007/070538-A2), anti-carboanhydrase IX antibodies or antigen-binding antibody fragments thereof which comprise the sequences of the three CDR regions of the light chain and the sequences of the three CDR regions of the heavy chain of the antibody 3ef2 (from WO 2007/070538-A2), anti-carboanhydrase IX antibodies or antigen-binding antibody fragments thereof which comprise the sequences of the three CDR regions of the light chain and the sequences of the three CDR regions of the heavy chain of the antibody 1e4 (from WO 2007/070538-A2), anti-carboanhydrase IX antibodies or antigen-binding antibody fragments thereof which comprise the sequences of the three CDR regions of the light chain and
• an antibody or antigen-binding fragment which comprises the amino acid sequence of the variable light and variable heavy chains of the antibody 3ee9, as indicated in WO 2007/070538-A2 in FIG. 4b on page 137, an antibody or antigen-binding fragment which comprises the amino acid sequence of the variable light and variable heavy chains of the antibody 3ef2, as indicated in WO 2007/070538-A2 in FIG. 4c on page 138 and in FIG. 4b on page 137, an antibody or antigen-binding fragment which comprises the amino acid sequence of the variable light and variable heavy chains of the antibody 1e4, as indicated in WO 2007/070538-A2 in FIG.
• an antibody or antigen-binding fragment which comprises the amino acid sequence of the variable light and variable heavy chains of the antibody 3a4, as indicated in WO 2007/070538-A2 in FIG. 4a on page 136, an antibody or antigen-binding fragment which comprises the amino acid sequence of the variable light and variable heavy chains of the antibody 3ab4, as indicated in WO 2007/070538-A2 in FIG. 4a on page 136, an antibody or antigen-binding fragment which comprises the amino acid sequence of the variable light and variable heavy chains of the antibody 3ah10, as indicated in WO 2007/070538-A2 in FIG.
• an antibody or antigen-binding fragment which comprises the amino acid sequence of the variable light and variable heavy chains of the antibody 3bb2, as indicated in WO 2007/070538-A2 in FIG. 4b on page 137, an antibody or antigen-binding fragment which comprises the amino acid sequence of the variable light and variable heavy chains of the antibody 1aa1, as indicated in WO 2007/070538-A2 in FIG. 4a on page 136, an antibody or antigen-binding fragment which comprises the amino acid sequence of the variable light and variable heavy chains of the antibody 5a6, as indicated in WO 2007/070538-A2 in FIG. 4b on page 137, and an antibody or antigen-binding fragment which comprises the amino acid sequence of the variable light and variable heavy chains of the antibody 5aa3, as indicated in WO 2007/070538-A2 in FIG. 4b on page 137.
• the anti-carboanhydrase IX antibody is antibody 3ee9 from WO 2007/070538-A2.
• the anti-carboanhydrase IX antibody or the antigen-binding antibody fragment comprises the amino acid sequences of the CDR regions of the variable heavy chain of the antibody 3ee9 (VH3-CDR1: GFTFSSYGMS; VH3-CDR2: GISSLGSTTYYADSVKG; VH3-CDR3: TGSPGTFMHGDH, see FIG.
• VLk1-CDR1 RASQDINNYLS
• VLk1-CDR2 YGASNLQS
• VLk1-CDR3 QQYYGRPT
• the anti-carboanhydrase IX antibody or the antigen-binding antibody fragment comprises the amino acid sequences of a variable heavy chain of the antibody 3ee9
• the anti-carboanhydrase IX antibody 3ee9 is an IgG antibody.
• the anti-carboanhydrase IX antibody 3 ee9 is an IgG1 antibody (3ee9-IgG1),
• amino acid sequence of the heavy chain comprises the following sequence:
• a further aspect of the present invention is the provision of the anti-carboanhydrase IX antibody 3ee9-IgG1.
• C4.4a antibodies and antigen-binding fragments are described below.
• the sequences of the antibodies are indicated in Table 1, with each line reproducing the respective CDR amino acid sequences of the variable light chain and of the variable heavy chain, respectively of the antibody listed in column 1.
• the amino acid sequences of the variable light chain and of the variable heavy chain, and the nucleic acid sequence of the antibody indicated in column 1 in each case, are also indicated.
• the anti-C4.4a antibodies or antigen-binding antibody fragments bind to the S1 domain S1 (amino acid position 1-85 of SEQ ID NO: 1) of C4.4a.
• anti-C4.4a antibodies or antigen-binding antibody fragments are cross-reactive with human C4.4a (SEQ ID NO:1) and with murine C4.4a (SEQ ID NO:2).
• the anti-C4.4a antibodies or antigen-binding antibody fragments thereof, after binding to a cell which expresses C4.4a, are internalized by the cell.
• the anti-C4.4a antibodies or antigen-binding antibody fragments compete with the antibody M31-B01 and/or with the antibody M20-D02-S-A for binding to C4.4a.
• Antibodies M31-B01 and M20-D02-S-A compete for binding to C4.4a.
• the antibodies B01-1 to B01-12 were prepared from M31-B01 by means of affinity maturation and compete with M31-B01 for binding to C4.4a.
• the antibodies D02-1 to D02-13 were prepared from M20-D02-S-A by means of affinity maturation and compete with M20-D02-S-A for binding to C4.4a.
• anti-C4.4a antibodies or antigen-binding antibody fragments comprise at least one, two or three of the CDR amino acid sequences given in Table 1 or Table 2.
• anti-C4.4a antibodies or antigen-binding antibody fragments comprise at least one, two or three CDR amino acid sequences of an antibody given in Table 1 or Table 2.
• anti-C4.4a antibodies or antigen-binding antibody fragments comprise at least one, two or three CDR amino acid sequences of the variable light chain and at least one, two or three CDR amino acid sequences of the variable heavy chain of an antibody given in Table 1 or Table 2.
• anti-C4.4a antibodies or antigen-binding antibody fragments comprise which are at least 50%, 60%, 70%, 80%, 90% or 95% identical with the CDR amino acid sequences of the variable light chain and with the CDR amino acid sequences of the variable heavy chain, of an antibody given in Table 1 or Table 2.
• the CDR sequences of the anti-C4.4a antibodies or antigen-binding antibody fragments comprise
• anti-C4.4a antibodies or antigen-binding antibody fragments comprise which are at least 50%, 60%, 70%, 80%, 90% or 95% identical with the variable light chain and with the variable heavy chain, of an antibody given in Table 1 or Table 2.
• anti-C4.4a antibodies or antigen-binding antibody fragments comprise the three CDR amino acid sequences of the variable light chain and the three CDR amino acid sequences of the variable heavy chain of an antibody given in Table 1 or Table 2.
• anti-C4.4a antibodies or antigen-binding antibody fragments comprise a variable light chain and/or a variable heavy chain of an antibody given in Table 1 or Table 2.
• anti-C4.4a antibodies or antigen-binding antibody fragments comprise the variable light chain and the variable heavy chain of an antibody given in Table 1 or Table 2.
• C4.4a antibodies and the antigen-binding antibody fragments are selected from the group consisting of
• antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 75-77 and which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 78-80 (B01-10)
• antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 5, 9 and 13 and which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 17, 21 and 25 M31-B01
• antibody which comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO: 7, 11 and 15 and which comprises the CDR sequences of the variable light chain represented by the sequences SEQ ID NO: 19, 23 and 27 (M60-G03)
• C4.4a antibodies and the antigen-binding antibody fragments are selected from the group consisting of
• anti-C4.4a antibodies comprise the light chain and the heavy chain of an antibody given in Table 2.
• the anti-C4.4a antibodies comprise the light chain and the heavy chain of an antibody given in Table 2.
• the C4.4a antibody is selected from the group consisting of
• a further aspect of the present invention is the provision of an anti-C4.4a IgG1 antibody which comprises the amino acid sequence of the light chain and of the heavy chain of an antibody given in Table 2.
• trastuzumab is a humanized antibody which is used for the treatment among other things of breast cancer.
• An antibody which binds the cancer target molecule CD20 is rituximab (Genentech).
• Rituximab (CAS number: 174722-31-7) is a chimeric antibody which is used for the treatment of Non-Hodgkin's Lymphoma.
• One example of an antibody which binds the cancer target molecule CD52 is alemtuzumab (Genzyme).
• Alemtuzumab (CAS number: 216503-57-0) is a humanized antibody which is used for the treatment of chronic lymphatic leukaemia.
• Binders particularly preferred in accordance with the invention are anti-mesothelin antibodies, more particularly human or humanized anti-mesothelin antibodies.
• the antibodies preferably have an affinity of at least 10 ⁇ 7 M (as Kd value; in other words preferably those with smaller Kd values than 10 ⁇ 7 M), preferably of at least 10 ⁇ 8 M, more preferably in the range from 10 ⁇ 9 M to 10 ⁇ 11 M.
• Kd values may be determined, for example, by means of surface plasmon resonance spectroscopy.
• the antibody-drug conjugates of the invention likewise exhibit affinities in these ranges.
• the affinity is preferably not substantially affected by the conjugation of the drugs (in general, the affinity is reduced by less than one order of magnitude, in other words, for example, at most from 10 ⁇ 8 M to 10 ⁇ 7 M).
• the antibodies used in accordance with the invention are also notable preferably for a high selectivity.
• a high selectivity exists when the antibody of the invention exhibits an affinity for the target protein which is better by a factor of at least 2, preferably by a factor of 5 or more preferably by a factor of 10, than for an independent other antigen, e.g. human serum albumin (the affinity may be determined, for example, by means of surface plasmon resonance spectroscopy).
• the antibodies of the invention that are used are preferably cross-reactive.
• the antibody used in accordance with the invention in order to be able to facilitate and better interpret preclinical studies, for example toxicological or activity studies (e.g. in xenograft mice), it is advantageous if the antibody used in accordance with the invention not only binds the human target protein but also binds the species target protein in the species used for the studies.
• the antibody used in accordance with the invention in addition to the human target protein, is cross-reactive to the target protein of at least one further species.
• species of the families of rodents, dogs and non-human primates Preferred rodent species are mouse and rat.
• Preferred non-human primates are rhesus monkeys, chimpanzees and long-tailed macaques.
• the antibody used in accordance with the invention in addition to the human target protein, is cross-reactive to the target protein of at least one further species selected from the group of species consisting of mouse, rat and long-tailed macaque ( Macaca fascicularis ).
• antibodies used in accordance with the invention which in addition to the human target protein are at least cross-reactive to the mouse target protein. Preference is given to cross-reactive antibodies whose affinity for the target protein of the further non-human species differs by a factor of not more than 50, more particularly by a factor of not more than ten, from the affinity for the human target protein.
• the antibodies of the invention that are used are additionally notable preferably for invariant binding to mesothelin.
• Invariant binding is notable, for example, by the fact that the antibody of the invention that is used binds to an epitope of mesothelin which cannot be masked by a further extracellular protein.
• a further extracellular protein is, for example, the protein Ovarian Cancer Antigen 125 (CA125).
• Antibodies used with preference are notable for the fact that their binding to mesothelin is not blocked by CA125.
• Anti-mesothelin antibodies are described for example in WO 2009/068204. These antibodies can be used in accordance with the invention.
• a further aspect of the present invention is the provision of a new anti-mesothelin antibody (MF-Ta) whose amino acid sequence comprises the CDR sequences of the variable heavy chain represented by the sequences SEQ ID NO:398 (HCDR1), SEQ ID NO:399 (HCDR2) and SEQ ID NO:400 (HCDR3) and the CDR sequences of the variable light chain represented by the sequences SEQ ID NO:401 (LCDR1), SEQ ID NO:402 (LCDR2) and SEQ ID NO:403 (LCDR3).
• MF-Ta new anti-mesothelin antibody
• amino acid sequence of the anti-mesothelin antibody MF-Ta or antigen-binding antibody fragments comprises the sequence of the variable heavy chain represented by the sequences SEQ ID NO:404 and the sequence of the variable light chain represented by the sequence SEQ ID NO:405.
• amino acid sequence of the anti-mesothelin antibody MF-Ta or antigen-binding antibody fragments comprises the sequence of the variable heavy chain which is encoded by the nucleic acid sequence SEQ ID NO:406, and the sequence of the variable light chain which is encoded by the nucleic acid sequence SEQ ID NO:407.
• amino acid sequence of the anti-mesothelin antibody MF-Ta comprises the sequence of the heavy chain represented by the sequences SEQ ID NO:408 and the sequence of the light chain represented by the sequence SEQ ID NO:409.
• amino acid sequence of the anti-mesothelin antibody MF-Ta comprises the sequence of the heavy chain which is encoded with a nucleic acid sequence SEQ ID NO:410, and the sequence of the light chain with is encoded with a nucleic acid sequence SEQ ID NO: 411.
• the binder is an anti-mesothelin antibody or antigen-binding antibody fragment, where the antibody binds to mesothelin and exhibits invariant binding.
• an anti-mesothelin antibody or antigen-binding antibody fragment comprises the amino acid sequences of the three CDR regions of the light chain and the amino acid sequences of the three CDR regions of the heavy chain of an antibody described in WOv2009/068204-A1 (Table 7; page 61-63).
• anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequences of the three CDR regions of the light chain and the sequences of the three CDR regions of the heavy chain of the antibody MF-Ta, anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequences of the three CDR regions of the light chain and the sequences of the three CDR regions of the heavy chain of the antibody MF-J (WO2009068204-A1; Table 7; page 61), anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequences of the three CDR regions of the light chain and the sequences of the three CDR regions of the heavy chain of the antibody MOR06640 (WO 2009/068204-A1; Table 7; page 61), anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequences of the three CDR regions of the light chain and the sequences of the three CDR regions of the heavy chain of the antibody MF-226 (
• anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequence of the variable light chain and the sequence of the variable heavy chain of the antibody MF-Ta, anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequence of the variable light chain and the sequence of the variable heavy chain of the antibody MF-J (WO 2009/068204-A1; Table 7; page 61), anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequence of the variable light chain and the sequence of the variable heavy chain of the antibody MOR06640 (WO 2009/068204-A1; Table 7; page 61), anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequence of the variable light chain and the sequence of the variable heavy chain of the antibody MF-226 (WO 2009/068204-A1; Table 7; page 61), anti-mesothelin antibodies or antigen-binding antibody fragments thereof which comprise the sequence of the variable light chain and the sequence
• trastuzumab is a humanized antibody which is used for the treatment inter alia of breast cancer.
• An antibody which binds the cancer target molecule CD20 is rituximab (Genentech).
• Rituximab (CAS number: 174722-31-7) is a chimeric antibody which is used for the treatment of non-Hodgkin's lymphoma.
• One example of an antibody which binds the cancer target molecule CD52 is alemtuzumab (Genzyme).
• Alemtuzumab (CAS number: 216503-57-0) is a humanized antibody which is used for the treatment of chronic lymphatic leukaemia.
• antibodies which bind to HER2 besides trastuzumab (INN 7637, CAS No: RN: 180288-69-1) and pertuzumab (Cas No: 380610-27-5), are antibodies as disclosed in WO 2009/123894-A2, WO 200/8140603-A2, or in WO 2011/044368-A2.
• An example of an anti-HER2 conjugate is trastuzumab-emtansine (INN No. 9295).
• Examples of antibodies which bind the cancer target molecule CD30 and can be used for the treatment of cancer are brentuximab, iratumumab and antibodies as disclosed in WO 2008/092117, WO 2008/036688 or WO 2006/089232.
• An example of an anti-CD30 conjugate is brentuximab vedotine (INN No. 9144).
• antibodies which bind the cancer target molecule CD22 and can be used for the treatment of cancer are inotuzumab or epratuzumab.
• anti-CD22 conjugates are inotuzumab ozagamycin (INN No. 8574), or anti-CD22-MMAE and anti-CD22-MC-MMAE (CAS RN: 139504-50-0 and 474645-27-7).
• antibodies which bind the cancer target molecule CD33 and can be used for the treatment of cancer are gemtuzumab or lintuzumab (INN 7580).
• An example of an anti-CD33 conjugate is gemtuzumab-ozagamycin.
• An example of an anti-NMB conjugate is glembatumumab vedotine (CAS RN: 474645-27-7).
• An example of an antibody which binds the cancer target molecule CD56 and can be used for the treatment of cancer e.g. multiple myeloma, small-cell carcinoma of the lung, MCC or ovarian carcinoma, is lorvotuzumab.
• An example of an anti-CD56 conjugate is lorvotuzumab mertansine (CAS RN: 139504-50-0).
• Examples of antibodies which bind the cancer target molecule CD70 and can be used for the treatment of cancer are disclosed in WO 2007/038637-A2 or WO 2008/070593-A2.
• An example of an anti-CD70 conjugate is SGN-75 (CD70 MMAF).
• An example of an anti-CD74 conjugate is milatuzumab-doxorubicin (CAS RN: 23214-92-8).
• an antibody which binds the cancer target molecule CD 19 and can be used for the treatment of cancer e.g. non-Hodgkin's lymphoma
• an anti-CD19 conjugate SAR3419
• Examples of antibodies which bind the cancer target molecule mucin-1 and can be used for the treatment of cancer are clivatuzumab or the antibodies disclosed in WO 2003/106495-A2, WO 2008/028686-A2.
• Examples of anti-mucin conjugates are disclosed in WO 2005/009369-A2.
• Examples of antibodies which bind the cancer target molecule CD138 and conjugates thereof which can be used for the treatment of cancer are disclosed in WO 2009/080829-A1, WO 2009/080830-A1.
• Examples of antibodies which bind the cancer target molecule integrin alphaV and can be used for the treatment of cancer are intetumumab (Cas RN: 725735-28-4), abciximab (Cas-RN: 143653-53-6), etaracizumab (Cas-RN: 892553-42-3) or the antibodies disclosed in U.S. Pat. No. 7,465,449, EP 19859-A1, WO 2002/012501-A1 or WO 2006/062779-A2.
• Examples of anti-integrin alphaV conjugates are intetumumab-DM4 and other ADCs disclosed in WO 2007/024536-A2.
• Examples of antibodies which bind the cancer target molecule TDGF1 and can be used for the treatment of cancer are the antibodies disclosed in WO 02/077033-A1, U.S. Pat. No. 7,318,924, WO 2003/083041-A2 and WO 2002/088170-A2.
• Examples of anti-TDGF1 conjugates are disclosed in WO 2002/088170-A2.
• Examples of antibodies which bind the cancer target molecule PSMA and can be used for the treatment of cancer, e.g. prostate carcinoma, are the antibodies disclosed in WO 97/35616-A1, WO 99/47554-A1, and WO 01/009192-A1.
• Examples of anti-PSMA conjugates are disclosed in WO 2009/026274-A1.
• Examples of antibodies which bind the cancer target molecule EPHA2, can be used for preparing a conjugate and can be used for the treatment of cancer are disclosed in WO 2004/091375-A2.
• an antibody which binds the cancer target molecule HLA-DOB is the antibody lym-1 (Cas-RN: 301344-99-0), which can be used for the treatment of cancer, e.g. non-Hodgkin's lymphoma.
• anti-HLA-DOB conjugates are disclosed for example in WO 2005/081711-A2.
• the compounds of the invention possess valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
• the binder-drug conjugates (ADCs) of the invention, of the formula (Ia) exhibit a high and specific cytotoxic activity with regard to tumour cells, as may be shown on the basis of the assays set out in the present experimental section (C-1. to C-7e.).
• This high and specific cytotoxic activity on the part of the binder-drug conjugates (ADCs) of the invention, of the formula (Ia) is achieved through the appropriate combination of the new N,N-dialkylauristatin derivative and binder with linkers which exhibit not only an enzymatically, hydrolytically or reductively cleavable predetermined break point, for the release of the toxophores, but also no such predetermined break point.
• stable linkers which have no enzymatically, hydrolytically or reductively cleavable predetermined break point for the release of the toxophores, and which, following uptake of the ADCs into the tumour cell and following complete intracellular, enzymatic breakdown of the antibody, still remain wholly or partly intact, the activity is confined very specifically to the tumour cell.
• Compatibility between ADCs and stable linkers presupposes, among other things, that the metabolites formed intracellularly can be formed with sufficient efficacy, are able to reach their target and are able there to develop their anti-proliferative activity on the target with sufficient potency, without being carried out of the tumour cell again beforehand by transporter proteins.
• the metabolites formed intracellularly after the compounds of the formula (Ia) of the invention have been taken up exhibit a reduced potential as a substrate with respect to transporter proteins, thereby suppressing their redistribution into the systemic circulation and hence the triggering of potential side effects by the toxophore itself. Furthermore, the innovative N-alkyl attachment maintains the basic character at the amino end of the monomethyl-auristatin peptide. Especially in the case of the binder-drug conjugates (ADCs) of the formula (Ia) of the invention that are linked via lysine side chains, the overall charge of the antibody remains constant, irrespective of the number of toxophore-linker loadings.
• ADCs binder-drug conjugates
• the binder-drug conjugates of the invention exhibit a high and specific cytotoxic activity with respect to tumour cells which express mesothelin.
• the activity with respect to tumour cells which do not express mesothelin is significantly weaker at the same time.
• the compounds of the invention are therefore suitable to a particular degree for the treatment of hyperproliferative diseases in humans and in mammals generally.
• the compounds are able on the one hand to inhibit, block, reduce or lower cell proliferation and cell division, and on the other hand to increase apoptosis.
• the hyperproliferative diseases for the treatment of which the compounds of the invention can be employed include in particular the group of cancer and tumour diseases.
• these are understood as meaning, in particular, the following diseases, but without being limited to them: mammary carcinomas and mammary tumours (ductal and lobular forms, also in situ), tumours of the respiratory tract (parvicellular and non-parvicellular carcinoma, bronchial carcinoma), cerebral tumours (e.g.
• tumours of the digestive organs oesophagus, stomach, gall bladder, small intestine, large intestine, rectum
• liver tumours including hepatocellular carcinoma, cholangiocellular carcinoma and mixed hepatocellular and cholangiocellular carcinoma
• tumours of the head and neck region larynx, hypopharynx, nasopharynx, oropharynx, lips and oral cavity
• skin tumours squamous epithelial carcinoma, Kaposi sarcoma, malignant melanoma, Merkel cell skin cancer and non-melanomatous skin cancer
• tumours of soft tissue including soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcomas and rhabdomyosarcomas
• tumours of the urinary tract tumours of the bladder, penis, kidney, renal pelvis and ureter
• tumours of the reproductive organs tumours of the reproductive organs (carcinomas of the endometrium, cervix, ovary, vagina, vulva and uterus in women and carcinomas of the prostate and testicles in men).
• proliferative blood diseases in solid form and as circulating blood cells such as lymphomas, leukaemias and myeloproliferative diseases, e.g.
• lymphomas acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myelogenic and hair cell leukaemia, and also AIDS-correlated lymphomas, Hodgkin's lymphomas, non-Hodgkin's lymphomas, cutaneous T-cell lymphomas, Burkitt's lymphomas and lymphomas in the central nervous system.
• Hyperproliferative diseases for the treatment of which the compounds of the invention can be preferably employed are CA9-overexpressing tumours, mammary carcinomas and mammary tumours (e.g. ductal and lobular forms, also in situ); tumours of the respiratory tract (e.g. parvicellular and non-parvicellular carcinoma, bronchial carcinoma), including preferably non-parvicellular carcinoma of the lung; cerebral tumours (e.g.
• tumours of the urinary tract include more preferably tumours of the kidneys and of the bladder; and/or tumours of the reproductive organs (carcinomas of the endometrium, cervix, ovary, vagina, vulva and uterus in women and/or carcinomas of the prostate and testicles in men), including more preferably carcinomas of the cervix and uterus.
• Hyperproliferative diseases for the treatment of which the compounds of the invention can be preferably employed are EGFR-overexpressing tumours, respiratory tract tumours (e.g. parvicellular and non-pavicellular carcinomas, bronchial carcinoma), including preferably non-parvicellular carcinoma of the lung; tumours of the digestive organs (e.g. oesophagus, stomach, gall bladder, small intestine, large intestine, rectum), including especially intestinal tumours; tumours of the endocrine and exocrine glands (e.g. thyroid and parathyroid glands, pancreas and salivary gland), including preferably pancreas; tumours of the head and neck region (e.g. larynx, hypopharynx, nasopharynx, oropharynx, lips, oral cavity, tongue and oesophagus); and/or gliomas.
• respiratory tract tumours e.g. parvicellular and non-pavicellular carcinomas, bronchial carcinoma
• Hyperproliferative diseases for the treatment of which the compounds of the invention can be preferably employed are mesothelin-overexpressing tumours, tumours of the reproductive organs (carcinomas of the endometrium, cervix, ovary, vagina, vulva and uterus in women and/or carcinomas of the prostate and testicles in men), including preferably ovarian carcinomas; tumours of the endocrine and exocrine glands (e.g. thyroid and parathyroid glands, pancreas and salivary gland), including preferably pancreas; respiratory tract tumours (e.g. parvicellular and non-parvicellular carcinoma, bronchial carcinoma), including preferably non-parvicellular carcinoma of the lung; and/or mesotheliomas.
• Hyperproliferative diseases for the treatment of which the compounds of the invention can be preferably employed are C4.4a-overexpressing tumours, squamous epithelial carcinomas (e.g. of the cervix, vulva, vagina, of the anal duct, endometrium, fallopian tube, penis, scrotum, of the oesophagus, breast, of the bladder, of the bile duct, endometrium, uterus and ovary); mammary carcinomas and mammary tumours (e.g. ductal and lobular forms, also in situ); tumours of the respiratory tract (e.g.
• parvicellular and non-parvicellular carcinoma, bronchial carcinoma including preferably non-parvicellular carcinoma of the lung, squamous epithelial carcinoma and adenocarcinoma of the lung; tumours of the head and neck region (e.g.
• tumours of the urinary tract include tumours of the bladder, penis, kidney, renal pelvis and ureter, squamous epithelial carcinomas of the bladder), including more preferably tumours of the kidneys and of the bladder; skin tumours (squamous epithelial carcinoma, Kaposi sarcoma, malignant melanoma, Merkel cell skin cancer and non-melanomatous skin cancer), including more preferably melanomas; tumours of the endocrine and exocrine glands (e.g.
• tumours of the digestive organs e.g. oesophagus, stomach, gall bladder, small intestine, large intestine, rectum), including especially colorectal carcinomas; and/or tumours of the reproductive organs (carcinomas of the endometrium, cervix, ovary, vagina, vulva and uterus in women and/or carcinomas of the prostate and testicles in men), including more preferably uterine carcinomas.
• treatment encompasses an inhibiting, delaying, stemming, alleviating, attenuating, restricting, reducing, suppressing, repressing or healing of an illness, a complaint, a disease, an injury or a disruption to health, the development, course or progress of such conditions and/or the symptoms of such conditions.
• therapy is understood here to be synonymous with the term “treatment”.
• prevention refers to the avoidance or reduction in the risk of acquiring, experiencing, suffering or having an illness, a complaint, a disease, an injury or a disruption to health, a development or progress of such conditions and/or the symptoms of such conditions.
• the treatment or prevention of an illness, complaint, disease, injury or disruption to health may be partial or complete.
• the present invention thus further provides the use of the compounds of the invention for the treatment and/or prevention of diseases, in particular the abovementioned diseases.
• the present invention furthermore provides the use of the compounds of the invention for the preparation of a medicament for the treatment and/or prevention of diseases, in particular the abovementioned diseases.
• the present invention furthermore provides the use of the compounds of the invention in a method for the treatment and/or prevention of diseases, in particular the above-mentioned diseases.
• the present invention furthermore provides a method for the treatment and/or prevention of diseases, in particular the abovementioned diseases, using an effective amount of at least one of the compounds of the invention.
• the anti-mesothelin binder-drug conjugate of the invention is used preferably for treating cancer in a patient, where the cancer cells of the patient that are to be treated have mesothelin expression. Treatment is administered more preferably to patients whose mesothelin expression in cancer cells is higher than in healthy cells.
• One method of identifying patients who respond advantageously to an anti-mesothelin binder-drug conjugate for the treatment of cancer involves determining the mesothelin expression in cancer cells of the patient.
• the mesothelin expression is determined by mesothelin gene expression analysis.
• the skilled person knows of methods for gene expression analysis such as, for example, RNA detection, quantitative or qualitative polymerase chain reaction or fluorescence in situ hybridization (FISH).
• FISH fluorescence in situ hybridization
• the mesothelin expression is determined by means of immunohistochemistry with an anti-mesothelin antibody.
• the immunohistochemistry is carried out preferably on formaldehyde-fixed tissue.
• the antibody for use in the immunohistochemistry is the same antibody which is also used in the conjugate.
• the antibody for use in the immunohistochemistry is a second antibody which—preferably specifically—recognizes the mesothelin target protein.
• the compounds according to the invention can be employed by themselves or, if required, in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesirable and unacceptable side effects.
• the present invention furthermore therefore provides medicaments comprising at least one of the compounds of the invention and one or more further drugs, in particular for the treatment and/or prevention of the abovementioned diseases.
• the compounds of the present invention can be combined with known antihyperproliferative, cytostatic or cytotoxic substances for the treatment of cancer diseases.
• Suitable drugs in the combination which may be mentioned by way of example are as follows:
• the compounds of the present invention can be combined with antihyperproliferative agents, which can be, by way of example—without this list being conclusive as follows:
• the compounds of the invention can also be combined in a very promising manner with biological therapeutics such as antibodies (e.g. avastin, rituxan, erbitux, herceptin).
• biological therapeutics such as antibodies (e.g. avastin, rituxan, erbitux, herceptin).
• the compounds of the invention can also achieve positive effects in combination with therapies directed against angiogenesis, such as, for example, with avastin, axitinib, recentin, regorafenib, sorafenib or sunitinib.
• Combinations with inhibitors of the proteasome and of mTOR and also with antihormones and steroidal metabolic enzyme inhibitors are likewise particularly suitable because of their favourable profile of side effects.
• the compounds according to the invention can moreover also be employed in combination with radiotherapy and/or surgical intervention.
• the present invention furthermore provides medicaments which comprise at least one compound of the invention, conventionally together with one or more inert, non-toxic, pharmaceutically suitable excipients, and the use thereof for the abovementioned purposes.
• the compounds of the invention can act systemically and/or locally. They can be administered in a suitable manner for this purpose, such as for example parenterally, possibly by means of inhalation, or as an implant or stent.
• the compounds of the invention can be administered in suitable administration forms for these administration routes.
• Parenteral administration can be effected with bypassing of an absorption step (e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbally) or with inclusion of an absorption (e.g. intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
• Administration forms which are suitable for parenteral administration include injection and infusion formulations in the form of solutions, suspensions, emulsions or lyophilizates. Parenteral administration is preferred, in particular intravenous administration.
• parenteral administration it has proved advantageous in the case of parenteral administration to administer amounts of from about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg of body weight to achieve effective results.
• Instrument Micromass QuattroPremier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9 ⁇ 50 mm ⁇ 1 mm; eluent A: 1 l water+0.5 ml 50% strength formic acid, eluent B: 1 l acetonitrile+0.5 ml 50% strength formic acid; gradient: 0.0 min 90% A ⁇ 0.1 min 90% A ⁇ 1.5 min 10% A ⁇ 2.2 min 10% A; flow rate: 0.33 ml/min; oven: 50° C.; UV detection: 210 nm.
• MS instrument Micromass ZQ
• HPLC instrument HP 1100 Series
• UV DAD column: Phenomenex Gemini 3 ⁇ 30 mm ⁇ 3.00 mm
• eluent A 1 l water+0.5 ml 50% strength formic acid
• eluent B 1 l acetonitrile+0.5 ml 50% strength formic acid
• flow rate 0.0 min 1 ml/min ⁇ 2.5 min/3.0 min/4.5 min 2 ml/min
• oven 50° C.
• UV detection 210 nm.
• MS instrument Waters ZQ; HPLC instrument: Agilent 1100 Series; UV DAD; column: Thermo Hypersil GOLD 3 ⁇ 20 mm ⁇ 4 mm; eluent A: 1 l water+0.5 ml 50% strength formic acid, eluent B: 1 l acetonitrile+0.5 ml 50% strength formic acid; gradient: 0.0 min 100% A ⁇ 3.0 min 10% A ⁇ 4.0 min 10% A ⁇ 4.1 min 100% A (flow rate 2.5 ml/min); oven: 55° C.; flow rate: 2 ml/min; UV detection: 210 nm.
• MS instrument Waters ZQ; HPLC instrument: Agilent 1100 Series; UV DAD; column: Thermo Hypersil GOLD 3 ⁇ 20 mm ⁇ 4 mm; eluent A: 1 l water+0.5 ml 50% strength formic acid, eluent B: 1 l acetonitrile+0.5 ml 50% strength formic acid; gradient: 0.0 min 100% A ⁇ 2.0 min 60% A ⁇ 2.3 min 40% A ⁇ 3.0 min 20% A ⁇ 4.0 min 10% A ⁇ 4.2 min 100% A (flow rate 2.5 ml/min); oven: 55° C.; flow rate: 2 ml/min; UV detection: 210 nm.
• MS instrument Waters (Micromass) Quattro Micro; Instrument HPLC: Agilent 1100 Series; column: YMC-Triart C18 3 ⁇ 50 ⁇ 3 mm; eluent A: 1 l water+0.01 mol ammonium carbonate, eluent B: 1 l acetonitrile; gradient: 0.0 min 100% A ⁇ 2.75 min 5% A ⁇ 4.5 min 5% A; oven: 40° C.; flow rate: 1.25 ml/min; UV detection: 210 nm.
• the title compound can be prepared in various ways according to literature methods; see, for example, Pettit et al., Synthesis 1996, 719; Shioiri et al., Tetrahedron Lett. 1991, 32, 931; Shioiri et al., Tetrahedron 1993, 49, 1913; Koga et al., Tetrahedron Lett. 1991, 32, 2395; Vidal et al., Tetrahedron 2004, 60, 9715; Poncet et al., Tetrahedron 1994, 50, 5345. It was prepared either as the free acid or as a 1:1 salt with dicyclohexylamine.
• the title compound can be prepared in various ways according to literature methods; see, for example, Pettit et al., J. org. Chem. 1994, 59, 1796; Koga et al., Tetrahedron Lett. 1991, 32, 2395; Shioiri et al., Tetrahedron Lett. 1991, 32, 931; Shioiri et al., Tetrahedron 1993, 49, 1913.
• the compound was prepared in analogy to starting compound 2a, except that the hydrogenation was performed without addition of 1N hydrochloric acid.
• the title compound was prepared by the literature method (A. Ritter et al., J. org. Chem. 1994, 59, 4602).
• the title compound can be prepared by literature methods (see, for example, H. King, J. Chem. Soc. 1942, 432); it is also commercially available.
• the title compound can be prepared by literature methods (see, for example, H. King, J. Chem. Soc. 1942, 432).
• the title compound can be prepared in Boc-protected form by the literature method (see, for example, C. Johnson et al., Tetrahedron Lett. 1998, 39, 2059); the deprotection was effected in a customary manner by treatment with trifluoroacetic acid and subsequent neutralization.
• the title compound was prepared by a literature method (A. Ritter et al., J. org. Chem. 1994, 59, 4602) proceeding from commercially available (1S,2R)-1-[(tert-butoxycarbonyl)amino]-2-phenylcyclopropanecarboxylic acid (C. Cativiela et al., Chirality 1999, 11, 583).
• reaction mixture was then poured into a mixture of semisaturated aqueous ammonium chloride solution and ethyl acetate.
• the organic phase was removed, washed successively with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. 620 mg (98% of theory) of the title compound were obtained.
• the mixture was stirred at RT for 16 h.
• the reaction mixture was then concentrated, and the residue was taken up in ethyl acetate and extracted by shaking first with 5% aqueous citric acid solution, then with 5% aqueous sodium hydrogencarbonate solution and subsequently with saturated sodium chloride solution.
• the organic phase was concentrated and the residue was purified by flash chromatography on silica gel with 16:4 dichloromethane/methanol as the eluent. The corresponding fractions were combined and the solvent was removed under reduced pressure.
• the filter residue was taken up in 5 ml of dioxane/water and the solution was adjusted to pH 11 with 1 N sodium hydroxide solution.
• a total of 349 mg (1.6 mmol) of di-tert-butyl dicarbonate were added in several portions, in the course of which the pH of the solution was kept at 11.
• the dioxane was evaporated off and the aqueous solution was adjusted to a pH of 2-3 with citric acid.
• the mixture was extracted twice with 50 ml each time of ethyl acetate.
• the organic phases were combined, dried over magnesium sulphate and concentrated under reduced pressure.
• the residue was taken up in diethyl ether and the of the title compound was precipitated with pentane.
• the solvent was removed by decantation.
• the residue was digested several times more with pentane and finally dried under high vacuum. 40 mg (97% of theory) of the title compound were thus obtained.
• N-[(benzyloxy)carbonyl]-N-methyl-L-threonine was released from 237 mg (0.887 mmol) of its dicyclohexylamine salt thereof by taking it up in ethyl acetate and extractive shaking with 5% aqueous sulphuric acid. The organic phase was dried over magnesium sulphate, filtered and concentrated.
• Starting Compound 1 was released from 600 mg (1.28 mmol) of the corresponding dicyclohexylammonium salt by dissolving the salt in 100 ml of ethyl acetate and extractive shaking, first with 50 ml of 0.5% sulphuric acid and then with saturated sodium chloride solution. Then the organic phase was dried over magnesium sulphate, filtered, concentrated and reacted immediately with benzyl L-phenylalaninate in analogy to the synthesis of Intermediate 7, and then deprotected.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Immunology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biochemistry (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Molecular Biology (AREA)
• Genetics & Genomics (AREA)
• Biophysics (AREA)
• Cell Biology (AREA)
• Crystallography & Structural Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Oncology (AREA)
• Reproductive Health (AREA)
• Gastroenterology & Hepatology (AREA)
• Microbiology (AREA)
• Mycology (AREA)
• Endocrinology (AREA)
• Hematology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Indole Compounds (AREA)
• Peptides Or Proteins (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Applications Claiming Priority (24)

Publications (1)

Family

ID=45976407

Family Applications (7)

Family Applications After (6)

Country Status (16)

Cited By (10)

Families Citing this family (59)