EP3233127A1 - Conjugués anticorps-principe actif (adc) d'inhibiteurs de la ksp ayant des anticorps anti-tweakr aglycosylés - Google Patents

Conjugués anticorps-principe actif (adc) d'inhibiteurs de la ksp ayant des anticorps anti-tweakr aglycosylés

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Publication number
EP3233127A1
EP3233127A1 EP15816395.6A EP15816395A EP3233127A1 EP 3233127 A1 EP3233127 A1 EP 3233127A1 EP 15816395 A EP15816395 A EP 15816395A EP 3233127 A1 EP3233127 A1 EP 3233127A1
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EP
European Patent Office
Prior art keywords
amino
alkyl
antibody
benzyl
cooh
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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EP15816395.6A
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German (de)
English (en)
Inventor
Hans-Georg Lerchen
Sven WITTROCK
Yolanda Cancho Grande
Beatrix Stelte-Ludwig
Anette Sommer
Sandra Berndt
Christoph Mahlert
Anne-Sophie Rebstock
Carsten TERJUNG
Simone Greven
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Bayer Pharma AG
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Bayer Pharma AG
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Publication of EP3233127A1 publication Critical patent/EP3233127A1/fr
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    • 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
    • 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
    • A61K31/02—Halogenated hydrocarbons
    • A61K31/025—Halogenated hydrocarbons carbocyclic
    • A61K31/03—Halogenated hydrocarbons carbocyclic aromatic
    • 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
    • A61K31/13—Amines
    • A61K31/131—Amines acyclic
    • 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
    • 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
    • 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
    • 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
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • ADCs Antibody-drug conjugates (ADCs) of KSP inhibitors with aglycosylated anti-TWEAK antibodies
  • the invention relates to binder-drug conjugates (ADCs) of kinesin spindle protein inhibitors, to active metabolites of these ADCs, to methods of producing these ADCs, to the use of these ADCs for the treatment and / or prevention of diseases and to the use of these ADCs for the preparation of medicaments for the treatment and / or prevention of diseases, in particular hyperproliferative and / or angiogenic diseases such as, for example, cancer.
  • ADCs binder-drug conjugates
  • Such treatments may be monotherapy or in combination with other medicines or other therapeutic measures.
  • Cancers are the result of uncontrolled cell growth of various tissues. In many cases, the new cells invade existing tissues (invasive growth) or they metastasize to distant organs. Cancers occur in various organs and often have tissue-specific disease courses. Therefore, the term cancer as a generic term describes a large group of defined diseases of various organs, tissues and cell types.
  • early stage tumors may be removed by surgical and radiotherapeutic measures.
  • metastatic tumors can only be treated palliatively by chemotherapeutic agents.
  • the goal here is to achieve the optimal combination of improving the quality of life and extending the lifetime.
  • ADCs antibody drug conjugates
  • cytotoxic agent itself or another cytotoxic metabolite formed therefrom is released within the tumor cell, where it can exert its direct and selective action
  • damage to normal tissue could be kept within significantly narrower limits compared to conventional cancer chemotherapy [See, eg, JM Lambert, Curr. Opin. Pharmacol., 5, 543-549 (2005); AM Wu and PD Senter, Nat. Biotechnol.
  • WO2012 / 171020 describes ADCs in which several toxophore molecules are linked to an antibody via a polymeric linker.
  • the substances SB 743921, SB 715992 (isospinesib), MK-0371, AZD8477, AZ3146 and ARRY-520 are mentioned in WO2012 / 171020 as potential toxophores.
  • Kinesin spindle protein inhibitors Kinesin spindle protein (KSP, also known as Eg5, HsEg5, KNSL1, or KIF11) is a kinesin-like motor protein that is essential for the function of the bipolar mitotic spindle. Inhibition of KSP leads to mitotic arrest and apoptosis for a prolonged period of time (Tao et al., Cancer Cell 2005 Jul 8 (1), 39-59).
  • KSP inhibitors After finding the first cell-derived KSP inhibitor, monastrol, KSP inhibitors have become established as a class of new chemotherapeutic agents (Mayer et al., Science 286: 971-974, 1999) and are the subject of a number of patent applications (eg, WO2006 / 044825 WO2006 / 002236, WO2005 / 051922, WO2006 / 060737, WO03 / 060064, WO03 / 040979, and WO03 / 049527).
  • KSP inhibitors since KSP is effective only in a short period of the mitosis phase, KSP inhibitors must be present in a sufficiently high concentration during this phase.
  • WO2014 / 151030 discloses ADCs with certain KSP inhibitors.
  • the invention provides conjugates of an aglycosylated or aglycosyl anti-TWEAKR antibody with compounds of the following formula (I), wherein one or more of the compounds of the formula (I) is linked to the antibody via a linker L or .
  • Aglycosylated antibodies are antibodies that have no glycans at the conserved N-binding site in the CH2 domain of the Fc region.
  • the antibody is preferably a human, humanized or chimeric monoclonal antibody.
  • Particularly preferred is an anti-TWEAKR antibody that specifically binds to amino acid D at position 47 (D47) of TWEAKR (SEQ ID NO: 169), especially anti-TWEAKR antibody TPP-2658.
  • R 1 is H, -L- # 1, -MOD or - (CH 2 ) 0 - 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , - (CH 2 CH 2 O) o-3- (CH 2 ) o-3Z '(for example - (CH 2 ) 0 - 3 Z'), or -CH ( CH 2 W) represents Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, NH 2 , SO 3 H, COOH, -NH-CO-CH 2 -CH 2 - CH (NH 2 ) COOH or - (CO-NH-CHY 4 ) i_ 3 COOH; where represents WH or OH,
  • Y 4 is linear or branched, optionally substituted with -NHCONH 2 , C 1-6 alkyl or optionally substituted with -NH 2 substituted aryl or benzyl;
  • R 2 represents H, -MOD, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • Z represents -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is H or -
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2, substituted C 1-6 alkyl or optionally -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y 6 linear or branched C1-6 is alkyl;
  • R 4 represents H, -L- # 1, -SG lys - (CO) 0- iR 4 ', -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • SG j y g represents a cleavable by lysosomal enzymes group, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a Ci-10-alkyl, Cs-io-aryl or Cö-io-aralkyl, C5 -10- heteroalkyl, Ci-io-alkyl-O-Cö-io-aryl, Cs-io-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkoxy, Ci-10-alkoxy, Cö- io aryloxy or COE-io-Araikoxy-, Cs-io-Heteroaralkoxy-, Ci- l o-alkyl-O-COE-io aryloxy, Cs-io-heterocycloalkoxy-group, one or more times by - NH 2 , -NH-alkyl, -N (alky
  • R 4 is -H, -alkyl (preferably Cl-12-alkyl), -CH 2 -COOH, -CH 2 -CH 2 -COOH, or -CH 2 -CH 2 -
  • Z represents -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is H or -
  • Y 4 is linear or branched, optionally with -NHCONH 2 substituted, C 6 -alkyl or optionally -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y 6 linear or branched represents Ci- 6 alkyl;
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR U - or -CHR U -CH 2 -, wherein R 11 is H, NH 2 , SO 3 H, COOH, SH, halogen (especially F or Cl), G- 4 alkyl, Ci- 4 haloalkyl, C1-4 alkoxy, hydroxyl-substituted C1-4 alkyl, COO (Ci_4 alkyl) or OH;
  • A represents CO, SO, S0 2 , S0 2 NH or CNNH;
  • R 3 represents -L- # 1, -MOD, or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably -L- # 1 or a Ci-10-alkyl-, C ⁇ - IO - aryl or C 10 -o-aralkyl, C 1-10 -heteroalkyl, C 1-10 -alkyl-O-C 10 -ol-aryl or C 5-10 -heterocycloalkyl group which is substituted by 1-3 -OH groups, 1-3 halogen atoms, 1-3 halogenated alkyl groups (each having 1-3 halogen atoms), 1-3 O-alkyl groups, 1-3-SH groups, 1-3-alkyl groups, 1- 3 -O-CO-alkyl groups, 1-3 -O-CO-NH-alkyl groups, 1-3 -NH-CO-alkyl groups, 1-3 -
  • alkyl is preferably C1-10 alkyl
  • R 5 is H, NH 2 , NO 2 , halogen (especially F, Cl, Br), -CN, CF 3 , -OCF 3 , -CH 2 F, -CH 2 F, SH or - (CH 2 ) 0 - 3 Z is wherein Z is -H, -OY 3 , -SY 3 , halogen, NHY 3 , -CO-NY ⁇ 2 , or -CO-OY 3 , wherein Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 ) o- 3 Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, S0 3 H, NH 2 or COOH;
  • R 6 and R 7 independently of one another are H, cyano, (optionally fluorinated) C 1-10 -alkyl, (optionally fluorinated) C 2-10 -alkenyl, (optionally fluorinated) C 2-10 -alkynyl, hydroxyl, NO 2, NH 2, COOH or halogen (especially F, Cl, Br),
  • R 8 (optionally fluorinated) C 1-10 -alkyl, (optionally fluorinated) C 2-10 -alkenyl, (optionally fluorinated) C 2-10 -alkynyl, (optionally fluorinated) C 4-10 -cycloalkyl or - (CH 2) o-2- (HZ 2 ) wherein HZ 2 is a 4 to 7 membered heterocycle having up to two heteroatoms selected from N, O and S, each of which may be substituted with -OH, CO 2 OH or NH 2;
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ;
  • R 1 , R 3 or R 4 represents -L- # 1 or (in the case of R 8 ), L represents the linker and # 1 represents the bond to the binder or derivative thereof, wherein MOD represents - (NR 10 ) n - (Gl) o -G 2 -H, wherein R 10 represents H or Ci-C alkyl;
  • r represents (where if Gl is -NHCO- or not NH2)
  • n 0 or 1
  • o 0 or 1
  • G2 is a straight-chain and / or branched hydrocarbon group having 1 to 10 carbon atoms which is mono- or polysubstituted by one or more of the groups -O-, -S-, -
  • R y is H, phenyl, C 1 -C 18 -alkyl, C 2 -C 10 -Q alkenyl, or C2-Ci () -Aikinyl, each with
  • the conjugates according to the invention may have chemically labile linkers, enzymatically labile linkers or stable linkers. Particularly preferred are stable linkers and cathepsin-cleavable linkers.
  • the invention further provides methods for preparing the conjugates of the invention as well as precursors and intermediates for the preparation.
  • the preparation of the conjugates according to the invention regularly comprises the following steps:
  • the attachment of the reactive group can also take place after the formation of an optionally protected KSP inhibitor-linker precursor conjugate.
  • succinimide-linked ADCs after conjugation according to Scheme 26 can be converted into the open-chain succinic acid amides which have a favorable stability profile.
  • conjugation of the linker precursor to a low molecular weight KSP inhibitor may be accomplished by substitution of a hydrogen atom on R 1 , R 3 or R 4 in formula (I) by the linker.
  • any functional groups present may also be present in protected form. Prior to the conjugation step, these protecting groups are removed by known methods of peptide chemistry.
  • the conjugation can be carried out chemically in various ways, as exemplified in Schemes 20 to 31 in the Examples. It is particularly possible, the low molecular weight KSP inhibitor for Optionally modify conjugation to the linker, eg, by introducing protecting groups or leaving groups for easier substitution.
  • the invention provides novel low molecular weight KSP inhibitors that are conjugated to an anti-TWEAKR antibody.
  • KSP inhibitors or their antibody conjugates have the following general formula (II):
  • R 1 is H, -L-BINDER, -MOD or - (CH 2 ) 0 - 3 Z, wherein Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY ⁇ 2 , or Represents -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , - (CH 2 CH 2 O) o-3- (CH 2 ) o- 3 Z '(for example - (CH 2 ) o- 3 Z'), or CH (CH 2 W) Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, NH 2 , SO 3 H, COOH, -NH-CO-CH 2 -CH 2 - CH (NH 2 ) COOH or - (CO-NH-CHY 4 ) i_ 3 COOH; where represents WH or OH,
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 , C 1 -6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl;
  • R 2 is H, -MOD, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z, or R 2 and R 4 together (to form a pyrrolidine ring) -CH 2 -CHR 10 - or -CHR 10 represents -CH 2 -, wherein R 10 represents H, NH 2 , SO 3 H, COOH, SH, or OH;
  • Z represents -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is H or -
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2, substituted C 1-6 alkyl or optionally -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y 6 linear or branched C1-6 is alkyl;
  • R 4 represents H, -L-BINDER, -SG lys - (CO) 0- iR 4 ', -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • SG j y S represents a cleavable by lysosomal enzymes group, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a Ci-io-alkyl, Cs-io-aryl or Cö-io-aralkyl, C5 - 10 - heteroalkyl, Ci-io-alkyl-O-Cö-io-aryl, Cs-io-heterocycloalkyl, heteroaryl, heteroaryl-alkoxy, Ci- 10 -alkoxy-, Cö- io aryloxy or COE-io-Araikoxy-, Cs-io-Heteroaralkoxy-, Ci- l o-alkyl-O-COE-io aryloxy, Cs-io-heterocycloalkoxy-group, one or more times by - NH 2 , -NH-alkyl,
  • Z represents -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 ) o- 3 Z ', and Y 3 is H or - (CH 2 ) 0 - 3 Z', where Z 'is H, S0 3 H, NH 2 or COOH;
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 , C 1 -6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y 6 linear or branched C 1 -6 alkyl;
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR U - or -CHR U -CH 2 -, wherein R 11 is H, NH 2 , SO 3 H, COOH, SH, halogen (especially F or Cl), G- 4 alkyl, Ci-zt haloalkyl, C1-4 alkoxy, hydroxyl-substituted C1-4 alkyl, COO (Ci_4 alkyl) or OH;
  • A represents CO, SO, S0 2 , S0 2 NH or CNNH;
  • R 3 represents -L-BINDER, -MOD, or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably -L-BINDER or a C 1-10 -alkyl-, C 10 -o-iodo -Aryl or C 10 -o-aralkyl, C 1-10 -heteroalkyl, C 1-10 -alkyl-O-C 10 -10-aryl or C 5-10 -heterocycloalkyl group which react with 1-3 -OH groups, 1-3 halogen atoms, 1-3 halogenated alkyl groups (each having 1-3 halogen atoms), 1-3 O-alkyl groups, 1-3 -SH groups, 1-3 -S-alkyl groups, 1-3 -O- CO-alkyl groups, 1-3 -O-CO-NH-alkyl groups, 1-3 -NH-CO-alky
  • alkyl is preferably C 1 - 10 - alkyl
  • R 5 is H, NH 2 , NO 2 , halogen (especially F, Cl, Br), -CN, CF 3 , -OCF 3 , -CH 2 F, -CH 2 F, SH or - (CH 2 ) 0 - 3 Z is wherein Z is -H, -OY 3 , -SY 3 , halogen, NHY 3 , -CO-NY ⁇ 2 , or -CO-OY 3 , wherein Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, S0 3 H, NH 2 or COOH;
  • R 8 is (optionally fluorinated) Ci-10 alkyl, (optionally fluorinated) C2 -io-alkenyl, (optionally fluorinated) C2 -io-alkynyl, (optionally fluorinated) C4-io-cycloalkyl or - ( CH 2 ) o- 2 - (HZ 2 ), wherein HZ 2 represents a 4 to 7 membered heterocycle containing up to two heteroatoms selected from N, O and S (preferably oxetane), each of which groups being substituted with -OH, C0 2 H or NH 2 may be substituted;
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; wherein L is a linker and BINDER is an aglycosylated anti-TWEAKR antibody, which binder may optionally be attached to a plurality of drug molecules, one or none of R 1 , R 3 and R 4 represents -L-Binder;
  • R 6 and R 7 are independently H, cyano, (optionally fluorinated) Ci-10 alkyl, (optionally fluorinated) C2-10- alkenyl, (optionally fluorinated) C2 -io-alkynyl, hydroxy, N0 2, NH 2 , COOH or halogen (especially F, Cl, Br), where -MOD is - (NR 10 ) n - (G) o -G 2 H, wherein
  • R is H or Ci-C, -alkyl
  • G is -NHCO-, -CONH- or ⁇ / (where if G is -NHCO- or
  • ⁇ / represents R lü is not NH 2
  • n 0 or 1
  • o 0 or 1
  • G2 is a straight-chain and / or branched hydrocarbon group having 1 to 10 carbon atoms which is mono- or polysubstituted by one or more of the groups -O-, -S-, -
  • FIG. 1 Alignment of the TWEAKR cysteine-rich domain (amino acids 34 to 68) of various species. (The numbers show the amino acid position in full-length constructs including the signal sequences; SEQ ID NO: 169).
  • FIG. 2 A - Schematic diagram of the structure of TWEAKR (SEQ ID NO: 169).
  • the diagram shows the extracellular domain (amino acids 28-80) (SEQ ID NO: 168) including the cysteine-rich domain (36-67), the transmembrane domain - TM (81-101), and the intracellular domain (102-129).
  • TPP-2202 the complete ectodomain (28-80), fused to the Fc domain of hlgGl.
  • TPP-2203 extracellular domain with N- and C-terminal truncation (34-68) fused to the Fc domain of hlgGl.
  • TPP-2203 is given two amino acids and one more amino acid at the C-terminal compared to the pure cysteine-rich domain to ensure proper folding.
  • P4A8 (TPP-1324) binds only to the full-length extracellular domain (TPP-2202).
  • the invention provides conjugates of an aglycosyl anti-TWEAKR antibody with one or more drug molecules, wherein the drug molecule is a kinesin spindle protein inhibitor (KSP inhibitor) linked to the antibody via a linker L.
  • KSP inhibitor kinesin spindle protein inhibitor
  • the conjugate according to the invention can be represented by the general formula
  • BINDER stands for the anti-TWEAKR antibody
  • L for the linker
  • KSP for the KSP inhibitor
  • n for a number from 1 to 50, preferably 1.2 to 20 and particularly preferably 2 to 8.
  • n is an average of the number of KSP inhibitor-linker conjugates per BINDER.
  • KSP-L preferably has the above-mentioned formula (I).
  • the linker is linked to various amino acids of the antibody. Particularly preferred is a bond to different cysteine residues of the binder.
  • the aglycolyzed anti-TWEAKR antibody is preferably a human, humanized or chimeric monoclonal antibody.
  • an anti-TWEAKR antibody which specifically binds to amino acid D at position 47 (D47) of TWEAKR (SEQ ID NO: 169), especially anti-TWEAKR antibody TPP-2658.
  • antibodies which can be used according to the invention antibodies which can be used according to the invention, KSP inhibitors which can be used according to the invention and linkers which can be used according to the invention are described which can be used without restriction in combination.
  • the binders which are in each case described as being preferred or particularly preferred can be used in combination with the KSP inhibitors respectively shown as being preferred or particularly preferred, if appropriate in combination with the linkers respectively shown as being preferred or particularly preferred.
  • Ci-io-alkyl in the context of the invention represents a linear or branched alkyl radical having 1 to 10 carbon atoms.
  • alkyl radical having 1 to 10 carbon atoms.
  • Cö-io-aryl- in the context of the invention is a mono- or bicyclic aromatic homocycle, for example phenyl and naphthyl.
  • Cö-io-aralkyl group is in the context of the invention for a monocyclic aromatic homocycle, exemplified phenyl, to which a Cl-C4-alkyl group is attached.
  • An exemplary C 10 -o-aralkyl group is benzyl.
  • C5-io-heteroaryl in the context of the invention is a mono- or bicyclic, aromatic heterocycle having a total of 6 to 10 ring carbon atoms, wherein the ring or rings one or two ring heteroatoms from the series N, O, S, SO and / or SO2 and is linked via a ring carbon atom or optionally a ring nitrogen atom.
  • pyridyl furanyl, pyrimidyl, imidazolyl, thienyl, thiophenyl, isoxazoyl, isothiazoyl, 1,2,3-oxadiazoyl, furazanyl, 1,2,3-triazoyl, 1,2,4-triazoyl, pyridazyl, pyrrolyl, triazinyl , Indolyl, quinolinyl, quinazolinyl, 1,3-benzodioxole, isoindolyl, indazolyl, 1H-pyrazolo [3,4-d] pyrimidyl, benzotriazolyl, isoquinolinyl, sinolinyl, phthalazinyl, pteredinyl, naphthyridinyl, benzimidazolinyl, benzothiazolinyl, benzoxazolinyl, 3,4 -Methylene
  • Mono- or bicyclic heterocycle is in the context of the invention for a mono- or bicyclic heterocycle having a total of 5 to 10 ring carbon atoms, wherein the ring or rings one to three ring heteroatoms from the series N, O, S, SO and contains or is linked via a ring carbon atom or optionally a ring nitrogen atom.
  • Examples include piperidyl, pyrrolinyl, morpholinyl, 3,4-methylenedioxyphenyl, and tetrahydrofuranyl.
  • Halogen atom in the context of the invention is F, Cl, Br, or I.
  • the conjugation of the KSP inhibitor to the antibody can be accomplished chemically in a variety of ways, as exemplified in Schemes 20 to 31 in the Examples.
  • it is possible to optionally modify the low molecular weight KSP inhibitor for conjugation to the linker e.g. by introducing protecting groups or leaving groups for easier substitution (so that in the reaction this leaving group is substituted by the linker and not an H atom).
  • the KSP inhibitor-linker molecule thus obtained (wherein the linker has a reactive group for coupling to the binder) can then be reacted with the binder to obtain a binding conjugate of the invention.
  • This procedure is exemplarily illustrated in the experimental part by means of a large number of examples.
  • R 1 is H, -L- # 1, -MOD or - (CH 2 ) 0 - 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , - (CH 2 CH 2 O) o-3- (CH 2 ) o-3Z '(for example - (CH 2 ) 0 - 3 Z'), or -CH ( CH 2 W) represents Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, NH 2 , SO 3 H, COOH, -NH-CO-CH 2 -CH 2 - CH (NH 2 ) COOH or - (CO-NH-CHY 4 ) i_ 3 COOH; where represents WH or OH,
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 , C 1 -6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl;
  • R 2 represents H, -MOD, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • Z represents -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is H or -
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 , C 1 -6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y 6 linear or branched C 1 -6 alkyl;
  • R 4 represents H, -L- # 1, -SG lys - (CO) 0- iR 4 ', -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • SGjy S is a group cleavable by lysosomal enzymes, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a C 1-10 alkyl, Cs-io-aryl or C 10 -o-aralkyl, C 5-10 - heteroalkyl, Ci-io-alkyl-O-Cö-io-aryl, Cs-io-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkoxy, Ci- 10 -alkoxy, Cö-io represents aryloxy or COE-io-Araikoxy-, Cs-io-Heteroaralkoxy-, Ci- l o-alkyl-O-COE-io aryloxy, Cs-io-heterocycloalkoxy group comprising one or more times with - NH 2 , -NH-alkyl, -N (alkyl
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 V 3 Z ', and Y 3 H or -
  • Y 4 is linear or branched, optionally substituted by -NHCONEb, C 1 -6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y 6 linear or branched C 1 -6 represents alkyl;
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR 10 - or -CHR 10 -CH 2 -, wherein R 10 is H, NH 2 , SO 3 H, COOH, SH, halogen (especially F or Cl), G- 4 alkyl, Ci-zt haloalkyl, C1-4 alkoxy, hydroxyl-substituted C1-4 alkyl, COO (Ci_4 alkyl) or OH;
  • A represents CO, SO, SO 2 , SO 2 NH or CNNH;
  • R 3 represents -L- # 1, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably a C 1-10 alkyl, C 10 -oaryl or Ce- 10-aralkyl, C5-io-heteroalkyl, Ci-io-alkyl-O-Cö-io-aryl or Cs-io-heterocycloalkyl group having 1-3 -OH groups, 1-3 halogen atoms , 1-3 halogenated alkyl groups (each having 1-3 halogen atoms), 1-3 O-alkyl groups, 1-3 -SH groups, 1-3-alkyl groups, 1-3
  • 0-CO-alkyl groups 1-3 -O-CO-NH-alkyl groups, 1-3 -NH-CO-alkyl groups, 1-3 -NH-CO-NH-alkyl groups, 1-3 -S ( 0) "- alkyl groups, 1-3 -SO 2 -NH-alkyl groups, 1-3 -NH-alkyl groups, 1-3 -N (alkyl) 2 groups, 1-3 -NH ((CH 2 CH 2 0) i _ 2 () H) groups, 1-3 NH 2 groups, or
  • Z is -H, halo, -OY 3 , -SY 3 , -NHY 3 , -CO-NY ⁇ 2 , or -CO-OY 3 , with Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 H, - (CH 2 ) o-3-CH (NHCOCH 3 ) Z', - (CH 2 ) may be illustrating, wherein Z 'H, 3 represents SO H, NH 2 or COOH, substituted (wherein "alkyl” is preferably C o-3-CH (NH 2) Z' 3 Z, or - - (CH 2) 0 ' 1 - 10 - alkyl);
  • R 5 is H, -MOD, NH 2 , NO 2 , halogen (especially F, Cl, Br), -CN, CF 3 , -OCF 3 , -CH 2 F, -CH 2 F, SH or - (CH 2 ) 0 - 3 represents Z, where Z is -H, -OY 3, -SY 3, halogen, NHY 3, -CO-NY ⁇ 2, or -CO-OY represents 3,
  • Y 1 and Y 2 independently of one another represent H, NH 2 , or - (CH 2 V 3 Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, S0 3 H, NH 2 or COOH represents;
  • R 6 and R 7 are independently H, cyano, (optionally fluorinated) Ci-io alkyl, (optionally fluorinated) C 2 - 10 - alkenyl, (optionally fluorinated) C2 -io-alkynyl, hydroxy, NO 2 , NH 2 , COOH or halogen (especially F, Cl, Br),
  • R (optionally fluorinated) Ci 10 alkyl, (optionally fluorinated) C2 -io-alkenyl, (optionally fluorinated) C2 -io-alkynyl, (optionally fluorinated) C t-io-cycloalkyl or - ( CH 2 ) o- 2 - (HZ 2 ), wherein HZ 2 represents a 4- to 7-membered heterocycle having up to two heteroatoms selected from N, O and S (preferably oxetane), each of these groups being substituted with -OH, CO 2 H or NH 2 may be substituted; wherein one of the substituents R 1 , R 3 and R 4 represents -L- # 1,
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; wherein -MOD represents - (NR 10 ) n - (GI) o -G2-H, wherein R 10 represents H or C 1 -C -alkyl;
  • G is -NHCO-, -CONH- or ⁇ / (where if G is -NHCO- or
  • ⁇ / represents, R is not NH2)
  • n 0 or 1
  • o 0 or 1
  • G2 is a straight-chain and / or branched hydrocarbon group having 1 to 10 carbon atoms which is mono- or polysubstituted by one or more of the groups -O-, -S-, -
  • R y is H, phenyl, C 1 -C 18 -alkyl, C 2 -C 10 -Q alkenyl , or C2-Ci () -Aikinyl, each with
  • one of the substituents R 1 or R 3 represents # 1.
  • R 4 is H or
  • R 4 H
  • R 1 represents H, -L- # 1, or - (CH 2 ) 0 - 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY 2 , or CO-OY 3 represents,
  • Y 1 and Y 2 independently of one another are H, NH 2 , - (CH 2 CH 2 O) o-3- (CH 2 ) o-3Z '(for example - (CH 2 ) o- 3 Z'), or -CH ( CH 2 W) represents Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, NH 2 , SO 3 H, COOH, -NH-CO-CH 2 -CH 2 - CH (NH 2 ) COOH or - (CO-NH-CHY 4 ) i_ 3 COOH; wherein represents WH or OH;
  • Y 4 is linear or branched, optionally substituted with-NHCONH 2 , Ci-6 alkyl or optionally substituted with -NH 2 substituted aryl or benzyl.
  • R 2 and R 4 independently of one another are H, -SG lys - (CO) 0- lR 4 ', -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • SG j y S represents a cleavable by lysosomal enzymes group, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a Ci-io-alkyl, Cs-io-aryl or Cö-io-aralkyl, C5 - 10 - heteroalkyl, Ci-io-alkyl-O-Cö-io-aryl, Cs-io-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkoxy, Ci- 10 -alkoxy-, Cö- io aryloxy or COE-io-aralkoxy, Cs-io-Heteroaralkoxy-, Ci- l o-alkyl-O-COE-io aryloxy, Cs-io-heterocycloalkoxy-group, one or more times by - NH 2 , -NH-alkyl,
  • R 2 and R 4 together (to form a pyrrolidine ring) -CH 2 -CHR U - or -CHR 11 - CH 2 - represent wherein R 11 is H, NH 2, S0 3 H, COOH, SH, halo (especially F or Cl), Cl alkyl, C M haloalkyl, C 1 -4 alkoxy, hydroxyl-substituted C w alkyl, COO (C w alkyl), or OH; or R 2 is H, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z and R 4 is -L- # 1 wherein Z is - H, halo, -OY 3 , -SY 3 , NHY 3 , -CO-NY ⁇ 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is H or - (CH 2 ) 0 - 3 Z', where Z 'is H, S0 3 H Represents NH 2 or COOH;
  • Y 4 is independently linear or branched, optionally substituted by -NHCONH 2 , C 1 -6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl, wherein Y 4 linear or branched, optionally substituted with -NHCONH 2 , C 1 - 6 represents alkyl or aryl or benzyl optionally substituted with -NH 2 and Y 5 represents H or -CO-CHY 6 -NH 2 , wherein Y 6 represents linear or branched C 1 -6 alkyl;
  • A represents CO, SO, S0 2 , S0 2 NH or CNNH;
  • R 3 represents an optionally substituted alkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably -L- # 1 or a C 1-10 -alkyl, C 1-10 -aryl or C 10 -o-aralkyl-, C5- 10 - heteroalkyl, Ci-io-alkyl-O-COE-io aryl or Cs-io-heterocycloalkyl group (with 1-3 -OH groups, 1-3 halogen atoms, 1-3 halogenated alkyl groups each having 1-3 halogen atoms) ,, 1-3 O-alkyl groups, 1-3 -SH groups, 1-3 -S-alkyl groups, 1-3 -O-CO-alkyl groups, 1-3 -O -CO-NH-alkyl groups, 1-3 -NH-CO-alkyl groups, 1-3 -NH-CO-NH-alkyl groups, 1-3 -S (0) "-
  • alkyl is preferably Ci-10-alkyl
  • R 5 is H, F, NH 2 , NO 2 , halogen, SH or - (CH 2 ) 0 - 3 Z, where Z is -H, halo, -OY 3 , -SY 3 , NHY 3 , -CO-NYC 2 , or is -CO-OY 3 ,
  • Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is H or - (CH 2 ) 0 - 3 Z', where Z 'is H, S0 3 H Represents NH 2 or COOH;
  • R 6 and R 7 are independently H, cyano, (optionally fluorinated) Ci-10 alkyl, (optionally fluorinated) C2-10- alkenyl, (optionally fluorinated) C2 -io-alkynyl, hydroxy or halogen,
  • R 8 represents (optionally fluorinated) C 1-10 -alkyl, (optionally fluorinated) C 1-10 -cycloalkyl or optionally substituted oxetane;
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; and their salts, solvates and salts of the solvates.
  • one of the substituents R 1 , R 3 or R 4 represents -L- # 1, where L is the linker and # 1 is the binding to the antibody is. That is, in the case of the conjugates, one of the substituents R 1 , R 3 or R 4 represents -L- # 1, wherein -L- # 1 represents the binding to the antibody.
  • the binder is preferably a human, humanized or chimeric monoclonal antibody or antigen-binding fragment thereof. In a preferred embodiment of the formula (I) or (Ia), one of the substituents R 1 or R 3 represents -L- # 1.
  • R 4 is H or -SG j y S - (CO ) oiR 4 ', where SG j y S and R 4 ' have the same meaning as above.
  • R 4 H
  • Corresponding cleavable groups are described in more detail below.
  • Particularly preferred are an anti-TWEAKR antibody specific to the Amino acid D at position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the anti-TWEAKR antibody
  • the group -L- # 3 may also be present in the compound, where L is the linker and # 3 is the reactive group for binding to antibodies.
  • Compounds with -L- # 3 are reactive compounds that react with the antibody.
  • # 3 is preferably a group that reacts with an amino or thiol group to form a covalent bond, preferably with the cysteine residue in a protein.
  • the cysteine residue in a protein may be present in the protein, introduced by biochemical methods, or preferably generated by prior reduction of disulfides of the binder.
  • CO carbonyl
  • R 1 is preferably -L- # l, H, -COOH, -CONHNH 2 , - (CH 2 ) i-3NH 2 , -CONZ "(CH 2 ) i- 3 NH 2 and - CONZ '' CH 2 COOH where Z "is H or NH 2 .
  • R 2 and R 4 are preferably H or R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR 11 - or -CHR U -CH 2 -, wherein R 11 is H or F. Also preferred as R 4 is -L- # 1, wherein -L- # 1 is a cleavable linker, preferably an intracellular enzymatically cleavable linker.
  • R 3 is preferably -L- # l or a Cno-alkyl, which optionally with -OH, O-alkyl, SH, S-alkyl, O-CO-alkyl, O-CO-NH-alkyl, NH- CO-alkyl, NH-CO-NH-alkyl, S (0) "- alkyl, S0 2 -NH-alkyl, NH-alkyl, N (alkyl) 2 , or NH 2 may be substituted (wherein alkyl is preferably C1-3 Alkyl means).
  • R 5 is preferably H or F.
  • R 6 and R 7 are preferably each independently H, (optionally fluorinated) Ci-3-alkyl, (optionally fluorinated) C 2 -4 alkenyl, (optionally fluorinated) C2 ⁇ alkynyl, hydroxyl or halogen.
  • R 8 is preferably a branched Ci-5-alkyl group, in particular a group of the formula - C (CH 3 ) 2 - (CH 2 ) o- 2- R y , wherein R y is -H, -OH, C0 2 H, or NH 2 , or a (optionally fluorinated) C 5-7 -cycloalkyl Particularly preferred is a group of the formula -C (CH 3) 3 or a cyclohexyl group.
  • R 9 is preferably H or F. Particular preference is given to compounds of the formula (I) or (Ia) in which
  • A is CO (carbonyl);
  • R 1 is H, -L- # 1, -COOH, -CONHNH 2, - (CH 2 ) i- 3 NH 2 , -CONZ "(CH 2 ) i- 3 NH 2 and -CONZ" CH 2 COOH, wherein Z '' H or NH 2 ;
  • R 2 and R 4 are H, or R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR U - or -CHR U -CH 2 -, wherein R 11 represents H or F; or R 4 is -L- # 1 and R 2 is H;
  • R 3 is particularly preferably substituted by -OH, O-alkyl, SH, S-alkyl, O-CO-alkyl, O-CO-NH-alkyl, NH-CO-alkyl, NH-CO-NH-alkyl, S (0 ) - alkyl, SO 2 -NH-alkyl, NH-alkyl, N (alkyl) 2 , or NH 2 may be substituted (wherein alkyl is preferably C 1 -3 alkyl);
  • R 5 is H or F
  • R 6 and R 7 independently represent H, (optionally fluorinated) Ci-3-alkyl, (optionally fluorinated) C 2 -4 alkenyl, (optionally fluorinated) C2 -4 alkynyl, hydroxy or halogen;
  • R 8 is a branched C 1-5 alkyl group or cyclohexyl
  • R 9 is H or F.
  • R 1 represents -L- # 1, COOH or H
  • R 2 and R 4 are H or R 2 and R 4 are together (to form a pyrrolidine ring) -CH 2 -CHR U - or -CHR U -CH 2 -, where R 11 is H, or R 4 -L- # l is and R 2 is H;
  • A represents CO, R 3 - (CH 2 ) OH, -CH (CH 3 ) OH, -CH 2 SCH 2 CH (COOH) NHCOCH 3 , -CH (CH 3 ) OCH 3 , a phenyl group containing 1-3 halogen atoms, 1- 3 amino groups or 1-3 alkyl groups (which may optionally be halogenated, may be substituted, or -L- # l represents,
  • R 6 and R 7 independently of one another represent H, C 1-3 -alkyl or halogen, in particular that R 6 and R 7 represent F;
  • R 8 is C 1-4 -alkyl (preferably tert-butyl) or cyclohexyl; and or
  • R 9 represents H.
  • R 1 represents -L- # 1, COOH or H
  • R 2 and R 4 together represent H or R 2 and R 4 (to form a pyrrolidine ring) -CH 2 -CHR 11 - or -CHR U -CH 2 -, wherein R 11 represents H,
  • A represents CO
  • R 3 is - (CH 2 ) OH, -CH (CH 3 ) OH, -CH 2 SCH 2 CH (COOH) NHCOCH 3 , -CH (CH 3 ) OCH 3 , a phenyl group containing 1-3 halogen atoms, 1- 3 amino groups or 1-3 alkyl groups (which may optionally be halogenated, may be substituted, or -L- # l represents,
  • R 5 represents H
  • R 6 and R 7 independently of one another represent H, C 1-3 -alkyl or halogen, in particular that R 6 and R 7 represent F;
  • R 8 is C 1-4 -alkyl (preferably tert-butyl).
  • R 9 represents H.
  • R 1 is H, -L-Binder, -MOD or - (CH 2 ) o- 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY I, Y 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , - (CH 2 CH 2 O) o-3- (CH 2 ) o-3Z '(for example - (CH 2 ) o- 3 Z'), or -CH ( CH 2 W) represents Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, NH 2 , SO 3 H, - COOH, -NH-CO-CH 2 -CH 2 -CH (NH 2 ) COOH or - (CO-NH-CHY 4 ) i- 3 COOH; where represents WH or OH,
  • Y 4 is linear or branched, optionally substituted with -NHCONH 2 , C 1-6 alkyl or optionally substituted with -NH 2 substituted aryl or benzyl;
  • R 2 is H, -MOD, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z, wherein Y 4 is linear or branched, optionally substituted by -NHCONH 2 , C 1-6 alkyl or optionally with - NH 2 represents substituted aryl or benzyl and Y 5 represents H or -CO-CHY 6 -NH 2 , where Y 6 represents linear or branched C 1-6 -alkyl,
  • Z represents -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is H or -
  • R 4 represents H, -L-Binder, -SG lys - (CO) 0- i-R 4 ', -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • SGiy S represents a group cleavable by lysosomal enzymes, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a Ci-10-alkyl, Cs-io-aryl or Cö-io aralkyl, C5-10 - heteroalkyl, Ci-io-Aikyl-O-Cö io-aryl, Cs io-heterocycloalkyl, heteroaryl, heteroaryl-alkoxy, Ci-10-alkoxy, Cö-io-aryloxy or C 10 -alkoxy, C 1-10 -heteroaralkoxy, C 1-10 -alkyl-O-C0-10-aryloxy, C 1-10 -heterocycloalkoxy group which may be mono- or polysubstituted with -NH 2 , -NH-alkyl , -N (alkyl) 2 , NH-
  • Z represents -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is H or -
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR 11 - or -CHR U -CH 2 -, wherein R 10 is H, NH 2 , SO 3 H, COOH, SH, halogen (especially F or Cl), G- 4 alkyl, Ci- 4 haloalkyl, C 1-4 alkoxy, hydroxyl-substituted C 1-4 alkyl, COO (C 1-4 alkyl) or OH;
  • A represents CO, SO, SO 2 , SO 2 NH or CNNH;
  • R 3 is -L-Binder, -MOD, or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably -L-BINDER or a C 1-10 -alkyl, C 10 -o -Aryl or C 10 -o-aralkyl, C 3-10 -heteroalkyl, C 1-10 -alkyl-O-C 10 -10-aryl or C 5-10 -heterocycloalkyl group which react with 1-3 -OH groups, 1-3 halogen atoms, 1-3 halogenated alkyl groups (each having 1-3 halogen atoms), 1-3 O-alkyl groups, 1-3 -SH groups, 1-3 -S-alkyl groups, 1-3 -O- CO-alkyl groups, 1-3 -O-CO-NH-alkyl groups, 1-3 -NH-CO-alkyl groups, 1-3
  • alkyl is preferably C 1 - 10 - alkyl
  • R 5 is H, NH 2 , NO 2 , halogen (especially F, Cl, Br), -CN, CF 3 , -OCF 3 , -CH 2 F, -CH 2 F, SH or - (CH 2 ) 0 - 3 Z is wherein Z is -H, -OY 3 , -SY 3 , halogen, NHY 3 , -CO-NY ⁇ 2 , or -CO-OY 3 , wherein Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 V 3 Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, S0 3 H, NH 2 or COOH;
  • R 6 and R 7 are independently H, cyano, (optionally fluorinated) Ci 10 alkyl, (optionally fluorinated) C 2 - 10 - alkenyl, (optionally fluorinated) C2 -io-alkynyl, hydroxy, NO 2 , NH 2 , COOH or halogen (especially F, Cl, Br),
  • R 8 is (optionally fluorinated) Ci 10 alkyl, (optionally fluorinated) C2 -io-alkenyl, (optionally fluorinated) C2 -io-alkynyl, (optionally fluorinated) C t-io-cycloalkyl or- (CH 2 ) o- 2 - (HZ 2 ), wherein HZ 2 represents a 4- to 7-membered heterocycle having up to two heteroatoms selected from N, O and S, each of which is -OH, CO 2 H or NH 2 may be substituted; R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; wherein -MOD - (NR 10 ) n - (Gl) o -G2-H, wherein
  • R is H or C 1 -C 3 alkyl; represents (where if Gl -NHCO- or
  • n 0 or 1
  • o 0 or 1
  • G2 is a straight-chain and / or branched hydrocarbon group having 1 to 10 carbon atoms which is mono- or polysubstituted by one or more of the groups -O-, -S-, -
  • R y is H, phenyl, C 1 -C 18 -alkyl, C 2 -C 10 -Q alkenyl, or C2-Ci o-alkynyl, each with
  • R 1 , R 3 and R 4 may be L-linkers wherein L is a linker and BINDER is the antibody is, where the antibody may be bound to multiple drug molecules.
  • R 1 represents -L-BINDER, H, or - (CH 2 ) o- 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY 2 , or -CO- OY 3 represents,
  • Y 1 and Y 2 independently of one another are H, NH 2 , - (CH 2 CH 2 O) o-3- (CH 2 ) 0 - 3 Z ', or -CH (CH 2 W) Z', and Y 3 H or - ( CH 2) 0 - 'group, wherein Z' Z 3 H, NH 2, S0 3 H, COOH, -NH-CO-CH 2 - CH 2 -CH (NH 2) COOH or - (CO-NH-CHY 4 ) represents i- 3 COOH; wherein represents WH or OH; wherein Y 4 is linear or branched, optionally substituted by -NHCONH 2 , C 1 -6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl;
  • R 2 and R 4 independently of one another are H, -SG lys - (CO) ol R 4 ', -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • R 2 and R 4 together (to form a pyrrolidine ring) -CH 2 -CHR U - or -CHR 11 - CH 2 -, or R 2 H, -CO-CHY 4 -NHY 5 or - (CH 2) 0 - Z represents 3 and R 4 -L- # l, wherein R 11 is H, NH 2, SO 3 H, COOH, SH, halo (especially F or Cl), C M alkyl, C M haloalkyl, C 1 -4 alkoxy , Hydroxyl-substituted C 1 -4 alkyl, COO (C 1-4 alkyl) or OH; wherein SGiy S represents a cleavable by lysosomal enzymes group, especially a group consisting of a di- or tripeptide, R 4 'is a Ci- 10 alkyl, Cs-io-aryl or COE-io-aralkyl, C5- 10 - heteroalkyl, Ci
  • Z represents -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY 2 , or -CO-OY 3 , wherein Y 1 and Y 2 independently of one another represent H, NH 2 , or - (CH 2 V 3 Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, S0 3 H, NH 2 or COOH represents;
  • Y 4 is linear or branched, optionally substituted by -NHCONEb, C 1 -6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y 6 linear or branched C 1 -6 represents alkyl;
  • A represents CO, SO, SO 2 , SO 2 NH or CNNH;
  • R 3 represents -L-BINDER or an optionally substituted alkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably -L-BINDER or a C 1 -10-alkyl, C 10 -ol-aryl or C 10 -alkyl group; io-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-O-Cö-io-aryl or Cs-io-heterocycloalkyl group having 1-3 -OH groups, 1-3 halogen atoms, 1 3 halogenated alkyl groups (each having 1-3 halogen atoms), 1-3 O-alkyl groups, 1-3-SH groups, 1-3-alkyl groups, 1-3 -O-CO-alkyl groups, 1-3 -O-CO-NH-alkyl groups, 1-3 -NH-CO-alkyl groups, 1-3 -NH-CO-alkyl groups
  • alkyl is preferably C 1 - 10 - alkyl
  • R 5 is H, F, NH 2 , NO 2 , halogen, SH or - (CH 2 ) 0 - 3 Z, where Z is -H, halogen, -OY 3 , -SY 3 , -NHY 3 , -CO-NY Represents ⁇ 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another represent H, NH 2 , or - (CH 2 V 3 Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, S0 3 H, NH 2 or COOH represents;
  • L is a linker and BINDER is a binder or derivative thereof, it being possible for the binder to be bound to a plurality of active substance molecules,
  • alkenyl (optionally fluorinated) C2 -io-alkynyl, hydroxy or halogen - R 6 and R 7 are independently H, cyano, (optionally fluorinated) Ci 10 alkyl, (optionally fluorinated) C 2 - 10 .
  • R 8 is (optionally fluorinated) Ci 10 alkyl, (optionally fluorinated) represents t-C io cycloalkyl, or optionally substituted oxetane;
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; and their salts, solvates and salts of the solvates.
  • KSP inhibitor-antibody conjugates are preferred according to the invention :: formula (IIb):
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 have the same meaning as in formula (II) or (IIa),
  • A is CO
  • B is a single bond, -O- CH 2 or -CH 2 -O-
  • R 20 is NH 2 > F, CF 3, or CH 3
  • n is 0, 1, or 2.
  • R 1 , R 3 , R 6 , R 7 , R 8 , and R 9 have the same meaning as in formula (II) or (IIa), wherein A is preferably CO and R 3 is -CH 2 OH, -CH 2 represents OCH 3 , CH (CH 3 ) OH or CH (CH 3 ) OCH 3 .
  • R 3, R 6, R 7, R 8 and R 9 have the same meaning as in formula (II) or (IIa), wherein A is preferably CO and R 3 is -CH 2 -S X - (CH 2) CM -CHY 5 -CC) OH, where x is 0 or 1, and Y 5 represents H or NHY 6 , wherein Y 6 represents H or -COCH 3 .
  • R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and R 9 have the same meaning as in formula (II) or (IIa), and R! -LB INDER represents.
  • R 1 or R 3 particularly preferably represent -MOD.
  • Formula (Ilj) has:
  • R 3 represents -L- # 1
  • A represents CO
  • R 6 , R 7 , R 8 and R 9 have the same meaning as in formula (I) have formula (Ilk):
  • R 1 represents -L- # 1
  • A is CO and R 3 is -CH 2 OH -;
  • R 3 , R 6 , R 7 , R 8 , and R 9 have the same meaning as in formula (I).
  • Z represents Cl or Br
  • R 1 represents - (CH 2 ) 0 - 3 Z, wherein Z represents -COOH or -CO-NY ⁇ 2 , wherein Y 2 - (CH 2 CH 2 O) o- 3 -
  • (CH 2 ) Q 3 Z 'and Y 1 represents H, NH 2 , or - (CH 2 CH 2 O) 0 - 3 - (CH 2 ) 0 3 Z';
  • Y 1 represents H
  • Y 2 represents - (CH 2 CH 2 O) 3 -CH 2 CH 2 Z 'and Z represents -COOH;
  • Y 1 represents H
  • Y represents 2 -CHzCHzZ 'and Z' represents - (CONHCHY 4 ) 2 COOH;
  • Y 1 represents H
  • Y 2 represents -CH 2 CH 2 Z '
  • Z' represents - (CONHCHY 4 ) 2 COOH and one represents Y 4 -propyl and the other represents - (CH 2 ) 3 -NHCONH 2 ;
  • Y 1 represents H
  • Y represents 2 -CHzCHzZ '
  • Z' represents - (CONHCHY 4 ) 2 COOH and one represents Y 4 -CH 3 and the other represents - (CH 2 ) 3 -NHCONH 2 ;
  • Y 4 represents linear or branched, optionally substituted by -NHCONH 2 , Ci-6 alkyl; at least one member of Y 4 is selected from z-propyl or -CH 3 .
  • Y 1 represents H
  • Y 2 represents -CHzCHzZ '
  • Z' represents -CONHCHY 4 COOH and optionally Y 4 with
  • -NH 2 represents substituted aryl or benzyl
  • Y 4 represents aminobenzyl
  • R 2 is - (CH 2 ) 0 - 3 Z and Z is -SY 3 ;
  • R 4 is -CO-CHY 4 -NHY 5 and Y 5 is H;
  • R 4 is -CO-CHY 4 -NHY 5 and Y 5 is -CO-CHY 6 -NH 2 ;
  • Y 4 is linear or branched, optionally substituted with -NHCONH 2 C 1 -6 alkyl. Furthermore, it is preferred if R 1 , R 2 or R 3 in formula (I) or (II) represents -MOD,
  • R 3 represents -MOD and R 1 or R 4 represents -L- # 1 and -L-BINDER, respectively, wherein -MOD represents - (NR 10 ) n - (GI) o -G 2 -H, wherein
  • R is H or C 1 -C 3 alkyl; represents (where if Gl -NHCO- or
  • n 0 or 1
  • o 0 or 1
  • G2 is a straight-chain and / or branched hydrocarbon group having 1 to 10 carbon atoms which is mono- or polysubstituted by one or more of the groups -O-, -S-, -
  • R y is H, phenyl, C 1 -C 18 -alkyl, C 2 -C 10 -Q alkenyl, or C2-Ci () -Aikinyl, each with
  • the group -MOD has a (preferably terminal) -COOH group, for example in a betaine group.
  • the group -MOD has the formula -CH 2 -S x - (CH 2) o-4 -CHY 5 -COOH, where x is 0 or 1, and Y 5 represents H or NHY 6 , where Y 6 is H or -COCH 3 represents.
  • R 1 represents -L-BINDER, H, or - (CH 2 ) o- 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY 2 , or -CO- OY 3 represents,
  • Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 CH 2 O) o-3- (CH 2 ) O 3 Z 'or - CH (CH 2 W) Z', and Y 3 is H or - (CH 2 ) 0 - 3 Z ', where Z' is H, NH 2 , SO 3 H, COOH, - NH-CO-CH 2 -CH 2 -CH (NH 2 ) COOH or - (CO-NH-CHY 4 ) i 3 represents COOH;
  • Y 4 is linear or branched, optionally substituted with -NHCONH 2 , C1-5 alkyl or aryl or benzyl optionally substituted with -NH2;
  • R 2 and R 4 are independently H, -SG lys - (CO) ol R 4 ', -CO-CHY 4 -NHY 5 or - (CH 2 ) o- 3 Z,
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR 11 - or -CHR 11 - CH 2 -, wherein R 11 is H, NH 2 , SO 3 H, COOH, SH, halogen (especially F or Cl), CI is alkyl, CM is haloalkyl, C1-4 is alkoxy, hydroxyl-substituted C is M, alkyl, COO (Cw alkyl) or OH;
  • SGiy S represents a group cleavable by lysosomal enzymes, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a Ci-10-alkyl, Cs-io-aryl or Cö-io aralkyl, C5-10 - heteroalkyl, Ci-io-Aikyl-O-Cö io-aryl, Cs io-heterocycloalkyl, heteroaryl, heteroaryl-alkoxy, Ci-10-alkoxy, Cö-io-aryloxy or C 10 -alkoxy, C 1-10 -heteroaralkoxy, C 1-10 -alkyl-O-C0-10-aryloxy, C 1-10 -heterocycloalkoxy group which may be mono- or polysubstituted with -NH 2 , -NH-alkyl , -N (alkyl) 2 , NH-
  • Z represents -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY 2 , or -CO-OY 3 , wherein Y 1 and Y 2 independently of one another represent H, NH 2 , or - (CH 2 V 3 Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, S0 3 H, NH 2 or COOH represents;
  • Y 4 is linear or branched, optionally substituted by -NHCONEb, C 1 -6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y 6 linear or branched C 1 -6 represents alkyl;
  • A represents CO, SO, SO 2 , SO 2 NH or CNNH;
  • R 3 represents -L-BINDER, an optionally substituted alkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, or -CH 2 -S x - (CH 2 ) o-4-CHY 5 -COOH, where x is 0 or 1 and Y 5 is H or NHY 6 , where Y 6 is H or -COCH 3 .
  • -L-BINDER or a C 1-10 -alkyl, C 10 -i-aryl or C 10 -o-aralkyl, C 1-10 -heteroalkyl, C 1-10 -alkyl-O-C0-io-aryl or C 5-10 -heterocycloalkyl group having 1-3 -OH groups, 1-3 halogen atoms, 1-3 halogenated alkyl groups (each having 1-3 halogen atoms), 1-3 O-alkyl groups, 1- 3 -SH groups, 1-3 -S-alkyl groups, 1-3 -O-CO-alkyl groups, 1-3 -O-CO-NH-alkyl groups, 1-3 - NH-CO-alkyl groups, 1 -3 -NH-CO-NH-alkyl groups, 1-3 -S (0) "- alkyl groups, 1-3 -SO 2 - NH-alkyl groups, 1-3 -NH-alkyl groups,
  • alkyl is preferably C 1 - 10 - alkyl
  • R 5 is H, F, NH 2 , NO 2 , halogen, SH or - (CH 2 ) 0 - 3 Z, where Z is -H, halogen, -OY 3 , -SY 3 , -NHY 3 , -CO-NY Represents ⁇ 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another represent H, NH 2 , or - (CH 2 V 3 Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, S0 3 H, NH 2 or COOH, where L is a linker and BINDER is the antibody, it being possible for the binder to be bound to a plurality of active substance molecules,
  • alkenyl (optionally fluorinated) C2 -io-alkynyl, hydroxy or halogen - R 6 and R 7 are independently H, cyano, (optionally fluorinated) Ci 10 alkyl, (optionally fluorinated) C 2 - 10 .
  • R 8 is (optionally fluorinated) Ci 10 alkyl, (optionally fluorinated) represents t-C io cycloalkyl, or optionally substituted oxetane; and R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; and their salts, solvates and salts of the solvates.
  • Z represents Cl or Br
  • R 1 is - (CH 2 ) 0 - 3 Z, where Z is -CO-NY ⁇ 2 , where Y 2 - (CH 2 CH 2 OCH 2) 2 Z 'and Y 1 is H, NH 2 , or - (CH 2 CH 2 O) o - 3 - represents (CH 2 ) 0 3 Z ';
  • Y 1 represents H
  • Y 2 represents - (CH 2 CH 2 O) 3 -CH 2 CH 2 Z 'and Z represents -COOH;
  • Y 1 represents H
  • Y 2 represents -CH 2 CH 2 Z 'and Z' represents - (CONHCHY 4 ) 2 COOH;
  • Y 1 represents H
  • Y 2 represents -CH 2 CH 2 Z '
  • Z' represents - (CONHCHY 4 ) 2 COOH and represents one representative of Y 4 isopropyl and the other represents - (CH 2 ) 3 -NHCONH 2 ;
  • Y 1 represents H
  • Y 2 represents -CH 2 CH 2 Z ', Z' - (CONHCHY 4 ) 2 COOH and represents one representative of Y 4 - CH 3 and the other represents - (CH 2 ) 3 -NHCONH 2 ;
  • Y 4 represents linear or branched, optionally substituted by -NHCONH 2 , C 1 -6 alkyl; at least one member of Y 4 is selected from z-propyl or -CH 3 .
  • Y 1 is H, Y 2 is -CH 2 CH 2 Z ', Z' is -CONHCHY 4 COOH and Y 4 is optionally aryl or benzyl substituted with -NH 2 ;
  • Y 4 represents an aminobenzyl
  • R 2 is - (CH 2 ) 0 - 3 Z and Z is -SY 3 ;
  • R 4 is -CO-CHY 4 -NHY 5 and Y 5 is H;
  • R 4 is -CO-CHY 4 -NHY 5 and Y 5 is -CO-CHY 6 -NH 2 ;
  • Y 4 is linear or branched optionally substituted -NHCONH 2 C 1 -6 alkyl.
  • R 1 is H, -L- # 1 or -L-BINDER, -MOD or - (CH 2 ) 0 - 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, CO-NY ⁇ 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , - (CH 2 CH 2 O) o-3- (CH 2 ) o-3Z '(for example - (CH 2 ) 0 - 3 Z'), or -CH ( CH 2 W) represents Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, NH 2 , SO 3 H, COOH, -NH-CO-CH 2 -CH 2 - CH (NH 2 ) COOH or - (CO-NH-CHY 4 ) i_ 3 COOH; where represents WH or OH,
  • Y 4 is linear or branched, optionally substituted by -NHCON, C 1 -6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl;
  • R 2 represents H, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z, wherein Z represents -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 V 3 Z ', and Y 3 H or -
  • Y 4 is independently linear or branched, optionally substituted by -NHCONH 2 , C 1 -6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y is 6 linear or branched C 1 -6 alkyl;
  • R 4 represents H or -L- # 1 and -L-BINDER, respectively (wherein -L- # 1 and -L-BINDER, respectively, is an enzymatically cleavable linker leading to the conversion of R 4 to H);
  • A represents CO, SO, SO 2 , SO 2 NH or CNNH;
  • R 3 -L represents # l or -L-BINDER, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably a Ci- 10 alkyl, COE -io-aryl, or COE-io-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-O-COE-io-aryl or C5-10 - heterocycloalkyl group with 1-3 -OH Groups, 1-3 halogen atoms, 1-3 halogenated alkyl groups (each having 1-3 halogen atoms), 1-3 O-alkyl groups, 1-3-SH groups, 1-3-S-alkyl groups, 1-3 - O-CO-alkyl groups, 1-3 -O-CO-NH-alkyl groups, 1-3 -NH-CO-alkyl groups, 1-3 -NH-CO-al
  • R 5 is H, -MOD, NH 2 , NO 2 , halogen (especially F, Cl, Br), -CN, CF 3 , -OCF 3 , -CH 2 F, -CH 2 F, SH or - (CH 2 ) 0 - 3 represents Z, where Z is -H, -OY 3, -SY 3, halogen, NHY 3, -CO-NY ⁇ 2, or -CO-OY represents 3,
  • Y 1 and Y 2 independently of one another represent H, NH 2 , or - (CH 2 V 3 Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, S0 3 H, NH 2 or COOH represents;
  • R 6 and R 7 are independently H, cyano, (optionally fluorinated) Ci 10 alkyl, (optionally fluorinated) C 2 - 10 - alkenyl, (optionally fluorinated) C2 -io-alkynyl, hydroxy, NO 2 , NH 2 , COOH or halogen (especially F, Cl, Br), R 8 (optionally fluorinated) Ci-io-alkyl, (optionally fluorinated) C 2 -io-alkenyl, (optionally fluorinated) C 2 -io-alkynyl, or (optionally fluorinated) C t-io-cycloalkyl; where one of the substituents R 1 and R 3 represents -L- # 1 or -L-BINDER, respectively,
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; wherein -MOD - represents (NR 10 ) n - (GI) o -G2-H, wherein R 10 represents H or Ci-C alkyl;
  • ⁇ / represents, R is not NH2)
  • n 0 or 1
  • o 0 or 1
  • G2 is a straight-chain and / or branched hydrocarbon group having 1 to 10 carbon atoms which is mono- or polysubstituted by one or more of the groups -O-, -S-, -
  • R y is H, phenyl, C 1 -C 18 -alkyl, C 2 -C 10 -Q alkenyl, or C2-Ci () -Aikinyl, each with
  • R 1 is H, -L- # 1 or -L-BINDER, -MOD or - (CH 2 ) 0 - 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, CO-NY ⁇ 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , - (CH 2 CH 2 O) o-3- (CH 2 ) o-3Z '(for example - (CH 2 ) 0 - 3 Z'), or -CH ( CH 2 W) represents Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, NH 2 , SO 3 H, COOH, -NH-CO-CH 2 -CH 2 - CH (NH 2 ) COOH or - (CO-NH-CHY 4 ) i_ 3 COOH; where represents WH or OH,
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 , C 1 -6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl;
  • R 2 represents H, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • Z represents -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is H or -
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 , C 1 -6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y 6 linear or branched C 1 -6 alkyl;
  • R 4 represents H
  • A represents CO, SO, S0 2 , S0 2 NH or CNNH;
  • R 3 -L represents # l or -L-BINDER, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably a Ci- 10 alkyl, COE -io-aryl, or COE-io-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-O-COE-io-aryl or C5-10 - heterocycloalkyl group with 1-3 -OH Groups, 1-3 halogen atoms, 1-3 halogenated alkyl groups (each having 1-3 halogen atoms), 1-3 O-alkyl groups, 1-3-SH groups, 1-3-S-alkyl groups, 1-3 - O-CO-alkyl groups, 1-3 -O-CO-NH-alkyl groups, 1-3 -NH-CO-alkyl groups, 1-3 -NH-CO-al
  • Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is H or - (CH 2 ) 0 - 3 Z', where Z 'is H, S0 3 H Represents NH 2 or COOH;
  • R 6 and R 7 are independently H or halogen (especially F, Cl, Br);
  • R 8 is (optionally fluorinated) Ci 10 alkyl; where one of the substituents R 1 and R 3 represents -L- # 1 or -L-BINDER, respectively,
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; wherein -MOD -CH 2 -S x - (CH 2) 0-4 -COOH -CHY 5, wherein x is 0 or 1, and Y 5 represents H or NHY 6, wherein Y6 is H or -COCH 3 group, and their Salts, solvates and salts of solvates.
  • R 1 and R 5 are H or -L- # 1;
  • R 2 and R 4 are H or R 2 and R 4 together (to form a pyrrolidine ring) -CH 2 -CHR 11 - or -CHR U -CH 2 - where R 11 is H; and
  • R 3 is CH 2 OH, CH (CH 3 ) OH or -L- # 1, wherein one of the substituents R 1 and R 3 represents -L- # 1.
  • R 1 is H or COOH
  • R 2 and R 5 represent H
  • R 4 represents -L- # 1
  • R 3 is CH 2 OH, or CH (CH 3 ) OH, wherein -L- # 1 is an enzymatically cleavable linker which results in the conversion of R 4 into H.
  • linkers fall into the group of in vivo cleavable linkers and into the group of in vivo stable linkers (see L. Ducry and B. Stump, Bioconjugate Chem. 21, 5-13 (2010)).
  • the in vivo cleavable linkers have an in vivo cleavable group, again distinguishing between chemically in vivo cleavable and enzymatically cleavable groups in vivo.
  • “Chemically in vivo cleavable” or “enzymatically in vivo cleavable” means that the linkers or groups in the bloodstream are stable and only on or in the target cell by the changed there chemical or enzymatic environment (lower pH; Glutathione concentration; Presence of lysosomal Enzymes such as cathepsin or plasmin, or glycosidases such as ⁇ -glucuronidases), so as to release the low molecular weight KSP inhibitor or a derivative thereof.
  • the chemically in vivo cleavable groups are in particular disulfide, hydrazone, acetal and aminal; the enzymatically in vivo cleavable groups, in particular those which are cleavable by lysosomal enzymes, are in particular 2-8-oligopeptide group, in particular a tri- or dipeptide group or glycosides.
  • Peptide cleavage sites are disclosed in Bioconjugate Chem. 2002, 13, 855-869, and Bioorganic & Medicinal Chemistry Letters 8 (1998) 3341-3346 and Bioconjugate Chem. 1998, 9, 618-626. These include, for example, valine-alanine, valine-lysine, valine-citrulline, alanine-lysine and phenylalanine-lysine (optionally with additional amide group).
  • the in vivo stable linkers are characterized by a high stability (less than 5% metabolites after 24 hours in plasma) and do not have the above-mentioned chemically or enzymatically cleavable groups in vivo.
  • the linker -L- preferably has one of the following basic structures (i) to (iv):
  • SG is a (chemically or enzymatically) in vivo cleavable group (especially disulfide, hydrazone, acetal, and aminal; or a cathepsin or plasmin cleavable 2-8 oligopeptide group)
  • SGI is an oligopeptide group, or preferably a dipeptide group
  • LI is independently in vivo stable organic groups
  • L2 stands for a coupling group to the binder or a single bond.
  • the coupling is preferably carried out on a cysteine residue or a lysine residue of the antibody.
  • the coupling may be to a tyrosine residue, glutamine residue or an unnatural amino acid of the antibody.
  • the unnatural amino acids may include, for example, aldehyde or keto groups (such as formyl glycine) or azide or alkyne groups (see Lan & Chin, Cellular Incorporation of Unnatural Amino Acids and Bioorthogonal Labeling of Proteins, Chem. Rev. 2014, 114, 4764-4806 ).
  • the administration of a conjugate according to the invention having a linker basic structure (iii) and coupling of the linker to a cysteine or lysine residue of the antibody leads by metabolization to cysteine or lysine derivatives of the following formulas: wherein LI is in each case bound to the low molecular weight KSP inhibitor, for example a compound of the formula (I), (Ia), (II), (IIa), (IIb), (IIca), (IId), (Ile), ( Ilf), (III) or (IV).
  • linker basic structure (i) when bound to the position R4, in particular when m 0.
  • L2 is preferably derived from a group reactive with the sulfhydryl group of the cysteine.
  • groups include haloacetyls, maleimides, aziridines, acryloyls, arylating compounds, vinylsulfones, pyridyl disulfides, TNB-thiols and disulfide reducing agents.
  • These groups typically react electrophilically with the sulfhydryl bond to form a sulfide (e.g., thioether) or disulfide bridge. Preference is given to stable sulfide bridges.
  • L2 is preferable
  • # 1 denotes the point of attachment to the sulfur atom of the antibody
  • # 2 denotes the point of attachment to the group L 1
  • R 2 represents COOH, COOR, COR, CONHR, CONR 2 (each R is Cl-3-alkyl), CONH 2, preferably COOH.
  • L2 is:
  • the bonds to a cysteine residue of the antibody are preferably more than 80%, more preferably more than 90% (in each case based on the total number of links of the linker to the antibody), particularly preferably in one of the two structures of the formula A3 or A4 ago.
  • the structures of the formula A3 or A4 are generally present together, preferably in a ratio of 60:40 to 40:60, based on the number of bonds to the antibody. The remaining bonds are then in the structure
  • LI is preferably represented by the formula
  • R 10 is H, NH 2 or Ci-C alkyl
  • n 0 or 1;
  • o 0 or 1
  • G2 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms of arylene groups and / or straight-chain and / or branched and / or cyclic alkylene groups which is mono- or polysubstituted by one or more of the groups -O-, -S-, -SO-, SO2, -NRY-,
  • NRYCO- -C (NH) NRy-, -CONRY-, -NRYNRY-, -SO 2 NRYNRY-, -CONRYNRY-, (wherein R y is H, phenyl, C 1 -C 18 -alkyl, C 2 -C 10 -Q alkenyl, or C2-Ci () -Aikinyl, each with
  • hydrocarbon chain including the side chains, if present, may be substituted by -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid.
  • G2 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms of arylene groups and / or straight-chain and / or branched and / or cyclic alkylene groups which is mono- or polysubstituted by one or more of the groups -O-, -S-, -SO-, S02, -NH-, -CO-, -NHCO-, -CONH-, -NMe-, -NHNH-, -SO2NHNH-, -CONHNH- and a 5 to 10ghedral, aromatic or non-aromatic heterocycle having up to 4 heteroatoms from N, O and S, or -SO- may be interrupted (preferably
  • hydrocarbon chain including the side chains, if present, may be substituted with -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid.
  • Rx is H, Ci-C3-alkyl or phenyl.
  • the binding to the KSP inhibitor and # 2 is the binding to the coupling group to the antibody (eg L2).
  • a straight-chain or branched hydrocarbon chain of arylene groups and / or straight-chain and / or branched and / or cyclic alkylene groups generally comprises an .alpha.,. Omega.-divalent alkyl radical having the respectively indicated number of carbon atoms. Examples which may be mentioned by way of example and are preferably: methylene, ethane-1,2-diyl (1,2-ethylene), propane-1,3-diyl (1,3-propylene), butane-1,4-diyl (1,4-diyl).
  • Butylene pentane-l, 5-diyl (1,5-pentylene), hexane-1,6-diyl (1,6-hexylene), heptane-l, 7-diyl (1,7-hexylene), octane l, 8-diyl (1,8-octylene), nonane-l, 9-diyl (1,9-nonylene), decane-l, 10-diyl (1,10-decylene).
  • alkylene groups in the hydrocarbon chain can also be branched, ie one or more H atoms of the abovementioned linear alkylene groups can optionally be substituted by C 1-10 -alkyl groups and thus form side chains.
  • the hydrocarbon chain may further contain cyclic alkylene groups (cycloalkanediyl), for example 1,4-cyclohexanediyl or 1,3-cyclopentanediyl. These cyclic groups may be unsaturated.
  • aromatic groups arylene groups
  • one or more H atoms may be substituted by Cl-10-alkyl groups be substituted. It is thus formed a hydrocarbon chain, which is optionally branched. This hydrocarbon chain has a total of 0 to 100 carbon atoms, preferably 1 to 50, particularly preferably 2 to 25 carbon atoms.
  • the side chains may be substituted with -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid.
  • the hydrocarbon chain can be mono- or polysubstituted by one or more of the groups -O-, -S-, -SO-, SO 2, -NH-, -CO-, -NHCO-, -CONH-, -NMe-, -NHNH-, -S02NHNH-, -CONHNH- and a 5 to lOgliedriger, aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from N, O and S, -SO- or -S02- be interrupted (preferably
  • the linker corresponds to the following formula:
  • ⁇ represents the binding to the binder peptide or protein
  • LI has the formula -NR 1, 1 ⁇ -, wherein
  • R 11 represents H or NH 2 ;
  • B represents - [(CH 2 ) x- (X 4 ) y ] w - (CH 2 ) z-,
  • Linker L preferred according to the invention has the following formula:
  • # 3 represents the binding to the drug molecule
  • # 4 represents binding to the binder peptide or protein
  • RH represents H or NH2
  • B represents - [(CH 2 ) x- (X 4 ) y ] w - (CH 2 ) z-,
  • z 1 to 5; and X 4 is -O-, -CONH-, -NHCO- or represents.
  • linkers are particularly preferred in conjugates of formula (I) or (II) in which the linker couples SGI to R4 by substitution of an H atom on Rl or in conjunction with a cleavable linker, i. R1-L- # 1 represents or R4 -SG1-L- # 1, where # 1 represents the binding to the antibody.
  • the bonds to a Cy residue of the antibody are preferably more than 80%, more preferably more than 90% (in each case based on the total number of bonds of the Linker to the antibody), particularly preferably in one of the two structures of the formula A5 or A6:
  • # 1 denotes the point of attachment to the sulfur atom of the antibody
  • # 2 denotes the point of attachment to the group L 1
  • R 22 is COOH, COOR, COR, CONR 2 , CONHR (where R is Cl-3-alkyl), CONH 2 , preferably COOH.
  • the structures of the formula A5 or A6 are generally present together, preferably in a ratio of 60:40 to 40:60, based on the number of bonds to the antibody. The remaining bonds are then in the structure
  • linker -L- attached to a cysteine side chain or cysteine residue have the following formula
  • ⁇ represents the binding to the drug molecule
  • ⁇ represents the binding to the binder peptide or protein
  • n 0, 1, 2, or 3;
  • n 0, 1 or 2;
  • p is 0 to 20;
  • o 0 or 1
  • G3 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms
  • Arylene groups and / or straight-chain and / or cyclic alkylene groups which is mono- or polysubstituted by one or more of the groups -O-, -S-, -SO-, SO 2, -NH-, -CO-, -NHCO-, - CONH -, -NMe-, -NHNH-, -SO 2 NHNH-, -CONHNH- and a 3 to 10-membered (preferably 5 to 10-membered), aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from N, O and S, -SO- or -S02- may be interrupted (preferably
  • NH2, NH-CNNH2, sulfonamide, sulfone, sulfoxide or sulfonic acid may be substituted.
  • n 1;
  • n 0;
  • o 0 or 1
  • s, t, v and w are each independently 0 to 20, and u is 0 or 1.
  • Preferred groups LI in the above formula ⁇ - (CO) m-L1-L2- ⁇ are the following, wherein each r independently of one another is a number from 0 to 20, preferably from 0 to 15, particularly preferably from 1 to 20, in particular preferably from 2 to 10:
  • linkers LI indicated in these lines are linked to a linker L2 which is selected from:
  • the bonds to a cysteine residue of the binder are preferably more than 80%, more preferably more than 90% (in each case based on the total number of bonds of the linker to the binder), particularly preferably in one of the two structures of the formula A7 or A8 before.
  • the structures of the formula A7 or A8 are generally present together, preferably in a ratio of 60:40 to 40:60, based on the number of bonds to the binder. The remaining bonds are then in the structure
  • conjugates with corresponding linkers have the following structures, where XI is CH, X2 C, and X3 is N, and LI has the abovementioned meaning, L2 and L3 have the same meaning as LI, AKl is an aglycosylated anti-TWEAKR antibody which is linked via a cysteine residue and n is a number from 1 to 10. Especially preferred is an aglycosylated anti-TWEAKR antibody which specifically binds to amino acid D at position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the anti-TWEAKR antibody. TWEAKR antibody TPP-2658.
  • the linker When the linker is attached to a lysine side chain or a lysine residue, it preferably has the following formula:
  • ⁇ represents the binding to the drug molecule
  • ⁇ represents the binding to the binder peptide or protein
  • SG is a cleavable group, preferably a 2-8 oligopeptide, especially, preferably a dipeptide,
  • L4 represents a single bond or a group - (CO) y -G4-, wherein y represents 0 or 1, and G4 represents a straight or branched hydrocarbon chain having 1 to 100 carbon atoms from arylene groups and / or straight-chain and / or branched and / or cyclic alkylene groups which is mono- or polysubstituted by one or more of the groups -O-, -S-, -SO-, SO 2 , -NH-, -CO-, -NHCO-, -CONH-, -NMe-, -NHNH- , -SO 2 NHNH-, -CONHNH- and a 5- to 10-membered aromatic or non-aromatic heterocycle may be interrupted with up to 4 heteroatoms selected from N, O and S, -SO- or -SO 2 - (preferably
  • NH2, NH-CNNH2, sulfonamide, sulfone, sulfoxide or sulfonic acid may be substituted.
  • linkers to a lysine residue are given in Table B below.
  • the preferred coupling site (R ⁇ R 5 ) is further specified.
  • the example numbers are given, in which find appropriate linker application.
  • conjugates with corresponding linkers have the following structures, wherein XI is CH, X2 C, and X3 N, and L4 have the meanings given above, AK2 is an antibody which is bonded via a lysine residue, and n is a number of 1 to 10 is. More preferably, AK2 is a human, humanized or chimeric monoclonal, aglycosylated anti-TWEAKR antibody or antigen-binding fragment thereof. Particularly preferred is an aglycosylated anti-TWEAKR antibody specific to amino acid D at position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the anti-TWEAKR antibody TPP-2658.
  • SGI or SG is particularly preferred
  • X is H, a G-io-alkyl group which may be optionally substituted with -NHCONH 2 , -COOH, -OH, NH 2 , NH-CNNH 2 , or sulfonic acid.
  • these groups LI can be exchanged by one of the groups LI given for the above formula ⁇ - (CO) m-Ll-L2- ⁇ .
  • L2 is a succinic acid amide or derived therefrom, this amide can be partially or completely pre-purified in the form of the hydrolyzed open-chain succinamide, as described above.
  • conjugates having the basic structure (i) have the following structure, wherein XI is CH, X2C, and X3 is N, LA has the same meaning as LI, AK1 is an aglycosylated anti-TWEAKR antibody bound via a cysteine residue is, and n is a number from 1 to 10.
  • XI is CH
  • X2C is N
  • LA has the same meaning as LI
  • AK1 is an aglycosylated anti-TWEAKR antibody bound via a cysteine residue is
  • n is a number from 1 to 10.
  • the anti-TWEAKR antibody which specifically binds to amino acid D at position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the aglycosylated anti-TWEAKR antibody TPP-2658.
  • the conjugates according to the invention are prepared by initially providing the low molecular weight KSP inhibitor with a linker. The intermediate thus obtained is then reacted with the binder (preferably antibody).
  • cysteine residue For the coupling to a cysteine residue, it is preferable to react one of the following compounds with the cysteine-containing binder, for example an antibody which has possibly been partially reduced for this purpose:
  • R represents -H or -COOH
  • K is linear or branched, optionally substituted with C I -C east alkoxy or -OH Ci- C ⁇ alkyl, and
  • XI CH, X2 C, and X3 is N, SGI, LI, L2, L3 and L4 have the same meaning as described above.
  • the tert-butyl group may be replaced by cyclohexyl.
  • the compound may be used, for example, in the form of its trifluoroacetic acid salt.
  • the antibody is preferably used in 2 to 12 fold molar excess over the binder.
  • lysine residue For the coupling to a lysine residue, one of the following compounds is preferably reacted with the lysine-containing binder such as an antibody:
  • succinimide-linked ADCs after conjugation can be converted into the open-chain succinic acid amides which have a favorable stability profile.
  • This reaction can be carried out at pH 7.5 to 9, preferably at pH 8, at a temperature of 25 ° C to 37 ° C, e.g. by stirring.
  • the preferred stirring time is 8 to 30 hours.
  • AK1 is a cysteine-linked aglycosylated anti-TWEAKR antibody
  • AK2 is a lysine-linked, aglycosylated anti-TWEAKR antibody. More preferably, AK1 and AK2 provide an aglycosylated anti-TWEAKR antibody that specifically positions to amino acid D. 47 (D47) from TWEAKR (SEQ ID NO: 169), in particular the aglycosylated anti-TWEAKR antibody TPP-2658.
  • Aglycosyl or aglycosylated antibodies are antibodies that have no glycans at the conserved N-binding site in the CH2 domain of the Fc region.
  • the aglycosylated anti-TWEAKR antibody is preferably a human, humanized or chimeric monoclonal antibody. Particularly preferred is an anti-TWEAKR antibody that specifically binds to amino acid D at position 47 (D47) of TWEAKR (SEQ ID NO: 169), especially anti-TWEAKR antibody TPP-2658.
  • the conjugation of the toxophore to the antibody is preferably via one or more sulfur atoms of cysteine residues of the antibody and / or via one or more NH groups of lysine residues of the antibody.
  • the antibody can be linked via a linkage with the linker.
  • the linkage of the antibody can be effected by means of a heteroatom of the binder.
  • Heteroatoms of the invention that can be used for linking are sulfur (in one embodiment via a sulfhydryl group of the antibody), oxygen (according to the invention by means of a carboxyl or hydroxyl group of the antibody), and nitrogen (in one embodiment via a primary or secondary amine or amide group of the antibody). These heteroatoms may be present in the natural antibody or introduced by chemical or molecular biological methods.
  • the linkage of the antibody with the toxophore has only a small influence on the binding activity of the antibody to the target molecule. In a preferred embodiment, the linkage has no influence on the binding activity of the antibody to the target molecule.
  • an immunoglobulin molecule preferably comprises one molecule of four Polypeptide chains, two heavy chains (H chains) and two light chains (L chains), which are typically linked by disulfide bridges.
  • Each heavy chain comprises a heavy chain variable domain (abbreviated VH) and heavy chain constant domain.
  • the heavy chain constant domain may include three domains CHI, CH2 and CH3.
  • Each light chain comprises a variable domain (abbreviated VL) and a constant domain.
  • the constant domain of the light chain comprises a domain (abbreviated to CL).
  • the VH and VL domains can be further subdivided into regions of hypervariability, also called complementarity determining regions (abbreviated to CDR) and regions of lower sequence variability (FR).
  • CDR complementarity determining regions
  • FR regions of lower sequence variability
  • Each VH and VL region typically consists of three CDRs and up to four FRs.
  • An antibody can be obtained from any suitable species, eg, rabbit, llama, camel, mouse, or rat.
  • the antibody is of human or murine origin.
  • an antibody can be human, humanized or chimeric.
  • monoclonal antibody refers to antibodies obtained from a population of substantially homogeneous antibodies, ie, individual antibodies of the population are identical except for naturally occurring mutations which can occur in small numbers.Monoclonal antibodies recognize with high specificity a single antigenic binding site The term monoclonal antibody does not refer to a particular manufacturing process.
  • the term "intact" antibody refers to antibodies comprising both an antigen-binding domain and the light and heavy chain constant domain
  • the constant domain may be a naturally occurring domain, or a variant thereof in which multiple amino acid positions are altered were.
  • modified intact antibody refers to intact antibodies that have been fused to another non-antibody polypeptide or protein via their amino terminus or carboxy-terminus via a covalent bond (eg, a peptide linkage) modified to introduce reactive cysteines at defined sites to facilitate coupling to a toxophore (see Junutula et al., Nat Biotechnol., 2008, 26 (8): 925-32).
  • a covalent bond eg, a peptide linkage
  • human antibody refers to antibodies that can be obtained from a human or are synthetic human antibodies
  • a "synthetic” human antibody is an antibody that is available in part or in full as a whole from synthetic sequences in silico that are based on the Analysis of human antibody sequences.
  • a humane For example, antibody may be encoded by a nucleic acid isolated from a library of antibody sequences of human origin. An example of such antibodies is in Söderlind et al., Nature Biotech. 2000, 18: 853-856.
  • humanized or “chimeric” antibody describes antibodies consisting of a non-human and a human sequence portion. In these antibodies, part of the sequences of the human immunoglobulin (recipient) is replaced by sequence portions of a non-human immunoglobulin (donor).
  • the donor is a murine immunoglobulin in many cases.
  • amino acids of the CDR of the recipient are replaced with amino acids of the donor. Sometimes amino acids of the framework are replaced by corresponding amino acids of the donor.
  • the humanized antibody contains amino acids that were not contained in either the recipient or the donor and that were inserted during optimization of the antibody.
  • the variable domains of the donor immunoglobulin are fused to the constant regions of a human antibody.
  • CDR complementarity determining region
  • Each variable region typically has three CDR regions, referred to as CDR1, CDR2 and CDR3.
  • Each CDR region may comprise amino acids as defined by Kabat and / or amino acids of a hypervariable loop defined by Chotia.
  • the Kabat definition includes, 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) variable heavy chain (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed.
  • Chotia includes, 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)).
  • a CDR may comprise amino acids from a CDR region as defined by Kabat and Chotia.
  • antibodies can be divided into different classes. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG and IgM, several of which can be broken down into other subclasses. (Isotypes), eg IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2.
  • the heavy chain constant domain corresponding to the different classes are referred to as [alpha / a], [delta / ⁇ ], [epsilon / ⁇ ], [gamma / ⁇ ] and [my / ⁇ ]. Both the three-dimensional structure and the subunit structure of antibodies are known.
  • the term "functional fragment” or "antigen-binding antibody fragment” of an antibody / immunoglobulin is defined as a fragment of an antibody / immunoglobulin (e.g., the variable domains of an IgG) that still encompasses the antigen-binding domains of the antibody / immunoglobulin.
  • the "antigen binding domain" of an antibody typically comprises one or more hypervariable regions of an antibody, eg the CDR, CDR2 and / or CDR3 region
  • the "framework” or “framework” region of an antibody may also bind to the antibody
  • the antigen binding domain comprises at least amino acids 4 to 103 of the variable light chain and amino acids 5 to 109 of the variable heavy chain, more preferably amino acids 3 to 107 of the variable light chain Chain and 4 to 111 of the variable heavy chain, particularly preferred are the complete variable light and heavy chains, ie amino acids 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 do not exhaustively include Fab, Fab ', F (ab') 2 and Fv fragments, diabodies, single domain antibodies (DAbs), linearae antibodies, single chain antibodies (single-chain Fv , abbreviated scFv); and multispecific, such as bi- and tri-specific, antibodies formed from antibody fragments CA 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). Antibodies other than "multi-specific” or “multi-functional” are those with identical binding sites.
  • Multispecific antibodies may be specific for different epitopes of an antigen or 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. Patent Nos. 4,474,893; 4,7 14,68 1; 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 can be designed to reduce or completely prevent the number of intermolecular disulfide interactions that occur between the Chi and CL domains.
  • Epitopic determinants refers to protein determinants that can specifically bind to an immunoglobulin or T cell receptor Epitopic determinants usually consist of chemically active surface groups of molecules such as amino acids or sugar side chains, or combinations thereof, and typically have specific 3-dimensional structural properties such as also specific charge characteristics. "Functional fragments” or “antigen-binding antibody fragments” may be fused to another non-antibody polypeptide or protein via their amino terminus or carboxy-terminus via a covalent bond (eg, a peptide linkage).
  • antibodies and antigen-binding fragments can be modified to introduce reactive cysteines at defined sites to facilitate coupling to a toxophore (see Junutula et al., Nat Biotechnol., 2008 Aug; 26 (8): 925-32) ).
  • Polyclonal antibodies can be prepared by methods known to those of ordinary skill in the art.
  • Monoclonal antibodies can be prepared by methods known to those of ordinary skill in the art (Köhler and Milstein, Nature, 256, 495-497, 1975).
  • Humanized human monoclonal antibodies can be prepared by methods known to those of ordinary skill in the art (Olsson et al., Meth Enzymol., 92, 3-16 and Cabilly et al., US 4,816,567 or Boss et al., US 4,816,397).
  • Antibodies of the invention can be obtained from recombinant antibody libraries, e.g. consists of the amino acid sequences of a variety of antibodies generated from a large number of healthy volunteers. Antibodies can also be produced by known recombinant DNA technology. The nucleic acid sequence of an antibody can be obtained by routine sequencing, or is available from publicly available databases.
  • an “isolated” antibody or binder has been purified from other components of the cell Contaminating components of a cell that may interfere with a diagnostic or therapeutic use are, for example, enzymes, hormones, or other peptidic or non-peptidic components of a cell an antibody or binder that has been purified to more than 95% by weight of the antibody or binder (determined, for example, by Lowry method, UV-Vis spectroscopy, or by SDS capillary gel electrophoresis) and an antibody that has been purified to such an extent at least fifteen amino acids of the amino terminus or an internal amino acid sequence can be determined or purified to homogeneity, the homogeneity being determined by SDS-PAGE under reducing or non-reducing conditions (the detection can be determined by Coomassie blue staining or preferably by silver staining)
  • an Ant iliklity normally produced by one or more purification steps.
  • the term "specific binding” or “specific binding” refers to an antibody or binder that binds to a predetermined antigen / target molecule.
  • Specific binding of an antibody or binder typically describes an antibody or binding with an affinity of at least 10 "7 M (as Kd value, so preferably those with smaller Kd values than 10 ⁇ 7 M), wherein the antibody or a binder has at least two-fold higher affinity for the predetermined antigen / target molecule than for a non-specific antigen / target molecule (eg, bovine serum albumin, or casein) which is not the predetermined antigen / target molecule or a closely related antigen / target molecule
  • the antibodies preferably have an affinity of at least 10 -7 M (as Kd value, that is preferably those having smaller Kd values than 10 -7 M), preferably of at least 10 -8 M, more preferably in the range of 10 -9 M to 10 -11
  • the Kd values can be determined by, for example, surface plasmon resonance spectroscopy.
  • the antibody-drug conjugates of the invention also have affinities in these areas.
  • the conjugation of the active ingredients preferably does not significantly affect the affinity (as a rule, the affinity is reduced by less than an order of magnitude, eg, at most from 10 -8 M to 10 -7 M).
  • the antibodies used according to the invention are furthermore preferably characterized by a high selectivity.
  • a high selectivity is present when the antibody according to the invention has an affinity to the target protein which is at least a factor of 2, preferably a factor of 5 or more preferably a factor of 10 than of an independent other antigen, e.g. human serum albumin (the affinity can be determined, for example, by surface plasmon resonance spectroscopy).
  • the antibodies used according to the invention are preferably cross-reactive.
  • the antibody used according to the invention binds not only the human target protein but also binds the species target protein in the species used for the studies .
  • the antibody used according to the invention is, in addition to the human target protein, cross-reactive to the target protein of at least one other species.
  • species of the family rodents, dogs and non-human primates are preferably used.
  • Preferred rodent species are mouse and rat.
  • Preferred non-human primates are rhesus monkeys, chimpanzees and long-tailed macaques.
  • the antibody used according to the invention is selected in addition to the human target protein cross-reactive to the target protein of at least one other species from the group of species consisting of mouse, rat and long-tailed macaque (Macaca fascicularis).
  • the human target protein cross-reactive to the target protein of at least one other species from the group of species consisting of mouse, rat and long-tailed macaque (Macaca fascicularis).
  • antibodies used according to the invention which, in addition to the human target protein, are at least cross-reactive with the mouse target protein.
  • the target molecule against which the binder e.g. an antibody or antigen-binding fragment thereof, a cancer target molecule.
  • cancer target molecule describes a target molecule that is more abundant on one or more types of cancer cells than non-cancerous cells of the same tissue type
  • the cancer targeting molecule is selectively present on one or more cancer cell types compared to non-cancerous cells of the same tissue type wherein selectively describes at least two-fold accumulation on cancer cells compared to non-cancer cells of the same tissue type (a "selective cancer target molecule”).
  • selective cancer target molecule allows the selective therapy of cancer cells with the conjugates of the invention.
  • TWEAKR extracellular cancer target molecule TWEAKR (SEQ ID NO: 169 (protein); SEQ ID NO: 170 (DNA).
  • Antibodies that bind cancer targeting molecules can be prepared by those of ordinary skill in the art by known methods such as chemical synthesis or recombinant expression. Cancer target binders can be purchased commercially or can be prepared by one of ordinary skill in the art by known methods such as chemical synthesis or recombinant expression. Further processes for the preparation of antibodies or antigen-binding antibody fragments are described in WO 2007/070538 (see page 22 "Antibodies").
  • phage display libraries eg Morphosys HuCAL Gold
  • Antigen-binding antibody fragments can be used (see WO 2007/070538, page 24 et seq., and AK Example 1 on page 70, AK Example 2 on page 72.)
  • Other methods of producing antibodies using DNA libraries from B cells are described on page 26 (WO 2007/070538)
  • Methods for humanizing antibodies are described on pages 30-32 of WO2007070538 and in detail in Queen, et al., Pro. Natl. Acad.
  • Harlow et al. (Monoclonal Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press (19881, Paul [Ed.]); Fundamental Immunology, (Lippincott Williams & Wilkins (1998)); and Harlow, et al., (Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1998).)
  • Those skilled in the art are familiar with the corresponding vectors, promoters and signal peptides necessary for the expression of a protein / antibody.
  • the antibodies of the invention are aglycosylated, i. they have no glycans at the conserved N-binding site in the CH2 domain of the Fc region.
  • aglycosylated antibodies such as the antibody TPP-2658
  • An example of this is the antibody TPP-2090, from which the antibody TPP-2658 was obtained by mutation on N297.
  • an anti-TWEAKR antibody or an antigen-binding fragment thereof is used, preferably one selected from those described below or aglycosylated by a suitable mutation.
  • those skilled in the art are aware of antibodies that bind to TWEAKR, see e.g. WO2009 / 020933 (A2) or WO2009140177 (A2).
  • the invention particularly relates to conjugates with antibodies or antigen-binding antibody fragments thereof or variants thereof which result in strong activation of the TWEAKR (SEQ ID NO: 169 (protein); SEQ ID NO: 170 (DNA)) leading to a strong induction of apoptosis in various cancer cells that show overexpression of TWEAKR.
  • TWEAKR SEQ ID NO: 169 (protein); SEQ ID NO: 170 (DNA)
  • TWEAKR agonistic activity with respect to the induction of apoptosis and inhibition of the proliferation of the previously described anti-TWEAKR antibodies (e.g., PDL-192) is limited and does not achieve the efficacy of the endogenous TWEAK ligand. This lack of agonistic activity is not due to diminished affinity since these antibodies bind to the TWEAKR with affinities that are in a similar range compared to the endogenous TWEAK ligand (Michaelson JS et al, MAbs., 2011 Jul-Aug; 3 (4 Culp PA et al, Clin Cancer Res.
  • a fully human antibody phage library (Hoet RM et al, Nat Biotechnol 2005; 23 (3): 344-8) was used to screen TWEAKR-specific human monoclonal antibodies of the present invention by protein panning (Hoogenboom HR, Nat Biotechnol 2005; 23 (3): 1105-16) with dimeric, Fc-fused extracellular domains of human and mouse TWEAKR as immobilized target. Eleven different Fab phages were identified and the corresponding antibodies were recloned into a mammalian IgG expression vector which provided the soluble FAb missing CH2-CH3 domains. After identifying preferred antibodies, they were expressed as full-length IgGs.
  • these constructs were transiently expressed in mammalian cells as described by Tom et al., Chapter 12 in Methods Express: Expression Systems edited by Micheal R. Dyson and Yves Durocher, Scion Publishing Ltd, 2007 (see AK Example 1).
  • the antibodies were purified by protein A chromatography and further characterized by their binding affinity to soluble monomeric TWEAKR by ELISA and BIAcore analysis as described in AK Example 2.
  • binding was tested by flow cytometry on a series of cell lines (HT29, HS68, HS578).
  • NFKB reporter gene assays were performed to examine the agonistic activity of all 11 identified antibodies (human IgGl).
  • TPP-883 The antibody with the strongest in vitro potency (TPP-883) was selected for further potency and affinity maturation (see AK Example 1 for details).
  • a single substitution variant with improved agonist activity was detected: G102T from CDR-H3.
  • the corresponding DNA thereof was recloned into a mammalian IgG expression vector and assayed for functional activity in the aforementioned NF-kappaB reporter gene assay. Finally, the sequences obtained were compared with human germ line sequences and deviations without significant influence on affinity and efficacy were adjusted.
  • TPP-2090 TPP-2149
  • TPP-2093 TPP-2148
  • TPP-2084 TPP -2077, TPP-1538, TPP-883, TPP-1854, TPP-1853, TPP-1857, and TPP-1858.
  • Antibodies of the invention may be further characterized by methods well known in the art, such as antibody phage display screening (eg, see Hoet RM et al, Nat Biotechnol 2005; 23 (3): 344-8), the well-established hybridoma technology (eg, see Kohler and Milstein Nature. 1975 Aug 7; 256 (5517): 495-7), or immunization of mice, among other immunization of hMAb mice (eg Veloclmmune mouse®).
  • antibody phage display screening eg, see Hoet RM et al, Nat Biotechnol 2005; 23 (3): 344-8
  • the well-established hybridoma technology eg, see Kohler and Milstein Nature. 1975 Aug 7; 256 (5517): 495-7
  • immunization of mice among other immunization of hMAb mice (eg Veloclmmune mouse®).
  • One embodiment of the invention is the provision of antibodies or antigen-binding antibody fragments thereof, or variants thereof, which exhibit strong caspase 3/7 induction in one or more TWEAKR-expressing cell lines.
  • the one or more TWEAKR-expressing cell lines are included in the group consisting of WiDr, A253, NCI-H322, HT29, and 786-0.
  • caspase 3/7 induction can be measured by standard methods known in the art, including in one embodiment, the "caspase 3/7 induction" of this invention is determined using caspase 3/7 solution activity determination (Promega, # G8093) and readout of luminescence on a VICTOR V (Perkin Elmer) , At the end of the incubation period, caspase 3/7 activity was determined and the caspase 3/7 induction factor was determined in comparison to untreated cells.
  • an antibody has "strong induction" of caspase 3/7 when the factor of induction is greater than 1.2, preferably greater than 1.5, more preferably greater than 1.8, even more preferably greater than 2, 1, more preferably greater than 2.5, anti-TWEAKR antibodies are provided which result in greater induction of caspase 3/7 in HT29 cells compared to previously described agonistic antibodies [eg PDL-192 (TPP-192)]. 1104), P4A8 (TPP-1324), 136.1 (TPP-2194)], and also compared to 300 ng / ml recombinant human TWEAK.
  • one embodiment of the invention is the provision of antibodies or antigen-binding antibody fragments thereof which specifically bind to a TWEAKR on a novel epitope prepared by selective binding to aspartate (D) at position 47 (D47) of TWEAKR (SEQ ID NO: 1). 169, see also Figure 1) is excellent.
  • the identified dependencies of certain TWEAKR amino acids for antibody interaction correlate with the agonistic activity determined for these antibodies.
  • the native ligand TWEAK shows potent activation of TWEAKR and, depending on leucine 46, binds to the cysteine-rich domain of TWEAKR (Pellegrini et al, FEBS 280: 1818-1829).
  • P4A8 shows very low agonistic activity and interacts at least in part with domains outside the cysteine-rich domain of TWEAKR.
  • PDL-192 shows moderate agonist activity and binds to the cysteine-rich domain, but to the TWEAK ligand site, depending on R56.
  • Antibodies of this invention e.g., TPP-2090
  • TWEAK binds dependent on L46.
  • TWEAK binds to a similar but distinguishable binding site ( Figure 7). Therefore, the antibodies of this invention which show strong agonistic activity bind to a new epitope (D47-dependent) which is associated with very strong agonistic activity.
  • the amino acid at position 47 (D47) of TWEAKR (SEQ ID NO: 169) is considered to be critical to the binding of the antibodies of the invention, meaning that the antibody specifically binds to D at position 47 (D47) of TWEAKR (SEQ ID NO: 169) binds if the antibody more than 20%, alternatively more than 30%, alternatively more than 40%, alternatively more than 50%, alternatively more than 60%, alternatively more than 70%, alternatively more than 80% Alternatively, greater than 90%, alternatively 100% of its ELISA signal is lost by altering this residue to alanine as described in AK Example 2 and FIG.
  • an antibody specifically binds to D at position 47 (D47) of TWEAKR (SEQ ID NO: 169) if the antibody is greater than 20%, alternatively greater than 30%, alternatively greater than 40%, alternatively greater than 50%. , alternatively more than 60%, alternatively more than 70%, alternatively more than 80%, alternatively more than 90%, alternatively loses 100% of its ELISA signal on TPP-2614 compared to TPP-2203.
  • an antibody binds specifically to the D at position 47 (D47) of TWEAKR (SEQ ID NO: 169) when the antibody loses more than 80% of its ELISA signal on TPP-2614 compared to TPP-2203.
  • TPP-2090 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 2 and a light chain region corresponding to SEQ ID NO: 1.
  • TPP-2658 is: an antibody comprising a heavy chain region corresponding to SEQ ID NO: 213 and a light chain region corresponding to SEQ ID NO: 1.
  • TPP-2149 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 12 and a light chain region corresponding to SEQ ID NO: 11.
  • TPP-2093 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 22 and a light chain region corresponding to SEQ ID NO: 21.
  • TPP-2148 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 32 and a light chain region corresponding to SEQ ID NO: 31.
  • TPP-2084 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 42 and a light chain region corresponding to SEQ ID NO: 41.
  • TPP-2077 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 52 and a light chain region corresponding to SEQ ID NO: 51.
  • TPP-1538 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 62 and a light chain region corresponding to SEQ ID NO: 61.
  • TPP-883 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 72 and a light chain region corresponding to SEQ ID NO: 71.
  • TPP-1854 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 82 and a light chain region corresponding to SEQ ID NO: 81.
  • TPP-1853 is: an antibody comprising a heavy chain region corresponding to SEQ ID NO: 92 and a light chain region corresponding to SEQ ID NO: 91.
  • TPP-1857 is: an antibody comprising a heavy chain region corresponding to SEQ ID NO: 102 and a light chain region corresponding to SEQ ID NO: 101.
  • TPP-1858 is: an antibody comprising a heavy chain region corresponding to SEQ ID NO: 112 and a light chain region corresponding to SEQ ID NO: 111.
  • TPP-2090 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 10 and a light chain variable region corresponding to SEQ ID NO: 9.
  • TPP-2658 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 10 and a light chain variable region corresponding to SEQ ID NO: 9.
  • TPP-2149 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 20 and a light chain variable region corresponding to SEQ ID NO: 19.
  • TPP-2093 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 30 and a light chain variable region corresponding to SEQ ID NO: 29.
  • TPP-2148 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 40 and a light chain variable region corresponding to SEQ ID NO: 39.
  • TPP-2084 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 50 and a light chain variable region corresponding to SEQ ID NO: 49.
  • TPP-2077 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 60 and a light chain variable region corresponding to SEQ ID NO: 59.
  • TPP-1538 is: an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 70 and a light chain variable region corresponding to SEQ ID NO: 69.
  • TPP-883 is an antibody comprising a heavy chain variable region according to SEQ ID NO: 80 and a light chain variable region corresponding to SEQ ID NO: 79.
  • TPP-1854 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 90 and a light chain variable region corresponding to SEQ ID NO: 89.
  • TPP-1853 is: an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 100 and a light chain variable region corresponding to SEQ ID NO: 99.
  • TPP-1857 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 10 and a light chain variable region corresponding to SEQ ID NO: 109.
  • TPP-1858 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 120 and a light chain variable region corresponding to SEQ ID NO: 1 19.
  • An aglycosylated anti-TWEAKR antibody or antigen binding fragment thereof which specifically binds to D at position 47 (D47) of TWEAKR (SEQ ID NO: 169).
  • variable heavy chain comprising: a heavy chain CDR1 encoded by an amino acid sequence comprising the formula PYPMX (SEQ ID NO: 171), wherein XI or M is; a heavy chain CDR2 encoded by an amino acid sequence comprising the formula YISPSGGXTHYADSVKG (SEQ ID NO: 172), wherein X is S or K; and a heavy chain CDR3 encoded by an amino acid sequence comprising the formula GGDTYFDYFDY (SEQ ID NO: 173); and a variable light chain comprising: a light chain CDR1 encoded by an amino acid sequence comprising the formula RASQSISXYLN (SEQ ID NO: 174), wherein X is G or S; a light chain CDR2 encoded by an amino acid sequence comprising the formula XASSLQS (SEQ ID NO: 175), wherein X is Q, A or N; and a light chain CDR3
  • variable heavy chain comprising the variable heavy chain CDR1 sequence as represented by SEQ ID NO: 6, the heavy chain CDR2 variable sequence as represented by SEQ ID NO: 7 and the variable CDR3 heavy chain sequence, as shown by SEQ ID NO: 8, as well as
  • variable light chain comprising the light chain variable CDR1 sequence represented by SEQ ID NO: 3, the light chain variable CDR2 sequence represented by SEQ ID NO: 4, and the light chain variable CDR3 sequence represented by SEQ ID NO 5 or a variable heavy chain comprising the variable heavy chain CDR1 sequence as represented by SEQ ID NO: 16; the heavy chain CDR2 variable sequence as represented by SEQ ID NO: 17; heavy chain as represented by SEQ ID NO: 18, and a variable light chain comprising the variable CDR1 light chain variable sequence represented by SEQ ID NO: 13, the light chain variable CDR2 sequence represented by SEQ ID NO: 14 and the variable CDR3 light chain sequence represented by SEQ ID NO: 15 or a variable heavy chain comprising the variable heavy chain CDR1 sequence as represented by SEQ ID NO: 26, the variable CDR2 sequence of s A heavy chain as shown by SEQ ID NO: 27, the heavy chain variable CDR3 sequence as represented by SEQ ID NO: 28, and a variable light chain comprising the variable CDR1 light chain variable sequence represented by SEQ ID NO:
  • the antibody or antigen binding fragment thereof comprising: a heavy chain variable sequence as represented by SEQ ID NO: 10 and a light chain variable sequence as represented by SEQ ID NO: 9 or a heavy chain variable sequence as represented by SEQ ID NO: 20; and a light chain variable sequence as represented by SEQ ID NO: 19 or a heavy chain variable sequence as represented by SEQ ID NO: 30, and a A light chain variable sequence as represented by SEQ ID NO: 29 or a heavy chain variable sequence as represented by SEQ ID NO: 40 and a light chain variable sequence as represented by SEQ ID NO: 39 or a variable sequence Sequence of the heavy chain as represented by SEQ ID NO: 50, as well as a variable sequence of the light chain as represented by SEQ ID NO: 49 or a variable sequence of the heavy chain A chain as represented by SEQ ID NO: 60 and a light chain variable sequence as represented by SEQ ID NO: 59 or a heavy chain variable sequence as represented by SEQ ID NO: 70 and a variable sequence of the light chain A chain
  • the antibody according to any one of the preceding embodiments which is an IgG antibody.
  • the antibody according to any one of the preceding embodiments, comprising: a heavy chain sequence as represented by SEQ ID NO: 2, and a light chain sequence as represented by SEQ ID NO: 1 or a heavy chain sequence represented by SEQ ID NO: 12, and a light chain sequence as represented by SEQ ID NO: 11 or
  • a heavy chain sequence as represented by SEQ ID NO: 112 and a light chain sequence as represented by SEQ ID NO: 111.
  • a heavy chain sequence as represented by SEQ ID NO: 213 and a sequence of the light chain as represented by SEQ ID NO: 1 or
  • the antibody or antigen binding fragment according to any one of the preceding embodiments which is a monoclonal antibody or an antigen binding fragment thereof.
  • the antibody or antigen binding fragment of any of the preceding claims which is a human, humanized or chimeric antibody or an antigen binding fragment.
  • anti-TWEAKR antibody TPP-2658 is particularly preferred.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • isotopic variants of a compound of the invention such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
  • Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and by the methods described below. Examples reproduced by appropriate isotopic modifications of the respective reagents and / or starting compounds are used.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid acetic acid, trifluoroacetic acid, propionic acid
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, as exemplified and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, / V-methylpiperidine, / V-methylmorpholine, arginine, lysine and 1,2-ethylenediamine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically).
  • Embodiment A is particularly preferred:
  • KSP-L- is a compound of the following formula (I), (Ia), (II), (IIa), (IIb), (IIc), (Ild), (Ile), (Iii), (IIj) , (Ilk) or the following formula (Ilf)
  • the binder is an aglycosylated anti-TWEAKR antibody (most preferably an anti-TWEAKR antibody specific to amino acid D at position 47 (D47) of TWEAKR (SEQ ID NO : 169), in particular the anti-TWEAKR antibody TPP-2658), and n is a number from 1 to 10:
  • A is CO (carbonyl);
  • R is -L- # 1, H, -COOH, -CONHNH 2, - (CH 2 ) i- 3 NH 2 , -CONZ "(CH 2 ) i- 3 NH 2 and -CONZ" CH 2 COOH, where Z ''H or NH 2 ;
  • R 2 and R 4 are H, or R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR U - or -CHR U -CH 2 -, wherein R 11 represents H or F; R 3 -L- # l or a Cl-10-alkyl, optionally with -OH, O-alkyl, SH, S-alkyl, O-CO-alkyl, O-CO-NH-alkyl, NH-CO -Alkyl, NH-CO-NH-alkyl, S (0) "- alkyl, S0 2 -NH-alkyl, NH-alkyl, N (alkyl) 2 , or NH 2 may be substituted (wherein alkyl is preferably C 1 -3 Alkyl);
  • R 5 is H or F
  • R 6 and R 7 independently represent H, (optionally fluorinated) Ci-3-alkyl, (optionally fluorinated) C 2 -4 alkenyl, (optionally fluorinated) C2 -4 alkynyl, hydroxy or halogen;
  • R 8 is a branched C 1-5 alkyl group
  • R 9 is H or F, wherein one of the substituents R 1 and R 3 represents -L- # 1, and
  • L represents the linker and # 1 represents the binding to the antibody, as well as salts, solvates and salts of the solvates of the ADC.
  • the linker is preferably a linker
  • n 0 or 1
  • ⁇ represents the binding to KSP
  • ⁇ represents the binding to the antibody
  • # 1 denotes the site of attachment to the sulfur atom of the antibody
  • # 2 denotes the site of attachment to the group L 1
  • LI represents the formula
  • R 10 is H, NH 2 or C 1 -C 3 alkyl
  • G represents -NHCO- or ⁇ /;
  • n 0 or 1
  • o 0 or 1
  • G2 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms of arylene groups and / or straight-chain and / or branched and / or cyclic alkylene groups which is mono- or polysubstituted by one or more of the groups -O-, -S-, -SO- , S02, -NH-, -CO-, -NHCO-, -CONH-, -NMe-, -NHNH-, -SO 2 NHNH-, -CONHNH- and a 3 to 10-membered, aromatic or non-aromatic heterocycle having up to 4 heteroatoms
  • - N N-CO- selected from N, O and S, or -SO- may be interrupted (preferably ⁇ /), the side chains, if present, with -NHCONH 2 , -COOH, -OH, -NH 2 , NH -CNNH 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted.
  • the binding to the KSP inhibitor and # 2 is the binding to the coupling group to the antibody (eg L2).
  • KSP-L- is a compound of the following formula (I), (Ia), (II), (IIa), (IIb), (IIc), (IId), (Ile), (IIIf), (III), (Ilj), (Ilk) or the following formula (Ilg) or the following formula (Ilg), the binder is an aglycosylated anti-TWEAKR antibody, and n is a number from 1 to 10:
  • A is CO (carbonyl);
  • R 2 and R 4 are H, or R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR U - or -CHR U -CH 2 -, wherein R 11 represents H;
  • R 5 is H or F
  • R 6 and R 7 independently represent H, (optionally fluorinated) Ci-3-alkyl, (optionally fluorinated) C 2 -4 alkenyl, (optionally fluorinated) C2 -4 alkynyl, hydroxy or halogen;
  • R 8 is a branched C 1-5 alkyl group
  • R 9 is H or F, wherein one of the substituents R 1 and R 3 represents -L- # 1, and
  • L represents the linker and # 1 represents the binding to the antibody
  • n 0 or 1
  • ⁇ represents the binding to KSP
  • ⁇ represents the binding to the antibody
  • # 1 denotes the site of attachment to the sulfur atom of the antibody
  • # 2 denotes the site of attachment to the group L 1
  • LI represents the formula
  • R 10 is H, NH 2 or C 1 -C 3 alkyl; Gl -NHCO- or represents;
  • G2 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms of arylene groups and / or straight-chain and / or branched and / or cyclic alkylene groups which is mono- or polysubstituted by one or more of the groups -O-, -S-, -SO- , S02, -NH-, -CO-, -NHCO-, -CONH-, -NMe-, -NHNH-, -SO 2 NHNH-, -CONHNH- and a 3 to 10-membered, aromatic or non-aromatic heterocycle having up to 4 heteroatoms
  • - N N-CO- selected from N, O and S, or -SO- may be interrupted (preferably ⁇ /), the side chains, if present, with -NHCONH 2 , -COOH, -OH, -NH 2 , NH -CNNH 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted,
  • # 1 is the binding to the CSF inhibitor and # 2 is the binding to the coupling group to the antibody (e.g., L2),
  • KSP-L- is a compound represented by the following formula (II), (IIa), (IIb), (IIc), (Ild), (Ile), (Ilf), (Ilg); (III), (IIj), (Ilk) or the following formula (IIh),
  • the binder is an aglycosylated anti-TWEAKR antibody, and n is a number from 1 to 10:
  • A is CO (carbonyl);
  • R 1 -L- # 1 is;
  • R 2 and R 4 are H, or R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR U - or -CHR U -CH 2 -, wherein R 11 represents H;
  • R 3 is a G- 10 -alkyl, optionally with -OH, O-alkyl, SH, S-alkyl, O-CO-alkyl, O-CO-NH-alkyl, NH-CO-alkyl, NH-CO -NH-alkyl, S (O) "- alkyl, S0 2 -NH-alkyl, NH-alkyl, N (alkyl) 2 , or NH 2 may be substituted (wherein alkyl is preferably C 1 -3 alkyl), or - MOD is;
  • R 10 is H or C 1 -C 3 -alkyl; represents (where if Gl -NHCO- or not NH2);
  • n 0 or 1
  • o 0 or 1
  • G2 is a straight-chain and / or branched hydrocarbon group having 1 to 10 carbon atoms which is mono- or polysubstituted by one or more of the groups -O-, -S-, -
  • R 5 is H or F
  • R 6 and R 7 independently represent H, (optionally fluorinated) Ci-3-alkyl, (optionally fluorinated) C 2 -4 alkenyl, (optionally fluorinated) C2 -4 alkynyl, hydroxy or halogen;
  • R 8 is a branched C 1-5 alkyl group
  • R 9 is H or F, where -L is the linker and # 1 is the bond to the antibody,
  • n 0 or 1
  • ⁇ represents the binding to KSP
  • ⁇ represents the binding to the antibody
  • # 1 denotes the site of attachment to the sulfur atom of the antibody
  • # 2 denotes the site of attachment to the group L 1
  • LI represents the formula
  • R 10 is H, NH 2 or C 1 -C 3 alkyl
  • G represents -NHCO- or ⁇ /;
  • n 0 or 1
  • o 0 or 1
  • S02- may be interrupted (preferably wherein hydrocarbon chain, including the side chains, if present, may be substituted by -NHCONH 2, -COOH, -OH, -NH 2 , NH-CNNH 2, sulfonamide, sulfone, sulfoxide, or sulfonic acid,
  • # 1 is the binding to the CSF inhibitor and # 2 is the binding to the coupling group to the antibody (e.g., L2),
  • the invention also provides binder-drug conjugates of the following general formula:
  • BINDER for the B aglycosylated anti-TWEAKR antibody L for the linker, WS for the active ingredient, preferably a KSP inhibitor, such as a KSP inhibitor according to the invention of one of the formulas (I), (Ia), ( II), (IIa), (IIb), (IIc), (Ild), (Ile), (Ilf), (Ilg), (Ith) (Iii),
  • m is a number from 1 to 2, preferably 1 and n is an integer from 1 to 50, preferably from 1.2 to 20 and more preferably from 2 to 8, wherein L has one of the following structures.
  • m is the number of drug molecules per linker and n an average of the number of drug-linker conjugates per BINDER. The sum of all WS present in a conjugate molecule is thus the product of m and n.
  • WS is an active substance which shows therapeutic effect in animals, preferably humans, a local or systemic effect.
  • active ingredients generally have a molecular weight of less than 5 kDa, preferably less than 1.5 kDa.
  • Preferred active ingredients are vinca alkaloids, auristatins, tubulysins, duocarmycins, kinase inhibitors, MEK inhibitors and KSP inhibitors.
  • Formula A4 wherein # 1 denotes the point of attachment to the sulfur atom of the binder, # 2 denotes the point of attachment with the active substance, x represents 1 or 2, and R 2 denotes COOH, COOR, COR (with R in each case C 1-3 -alkyl), CONH2, Br, preferably represents COOH ,.
  • LI has the same meaning as above.
  • -L- # 2 is represented by the following formula:
  • R 10 is H, NH 2 or GC 3 alkyl
  • ⁇ / represents, RIO is not NH2)
  • n 0 or 1
  • o 0 or 1
  • G2 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms of arylene groups and / or straight-chain and / or branched and / or cyken alkylene groups which is mono- or polysubstituted by one or more of the groups -O-, -S-, -SO- , SO2, -NRY-,
  • NRYCO- -C (NH) NRy-, -CONRY-, -NRYNRY-, -SO 2 NRYNRy-, -CONRYNRy-, (wherein R y is H, phenyl, C 1 -C 12 -alkyl, C 2 -C 10 -Q alkenyl, or C2-Ci represents Q-alkynyl, each with
  • hydrocarbon chain including the side chains may be substituted with -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH 2, sulfonamide, sulfone, sulfoxide, or sulfonic acid.
  • Rx is H, Ci-C-alkyl or phenyl.
  • the bonds to a cysteine residue of the antibody are preferably more than 80%, more preferably more than 90%, particularly preferably (based on the total number of linker bonds to the antibody) one of the two structures of the formula A3 or A4 ago.
  • conjugates with the linkers of formula A3 or A4 can be obtained by coupling the antibodies to the corresponding bromo derivatives of the following formulas A3 'or A4':
  • the invention also provides binder-drug conjugates of the following general formula:
  • m is the number of drug molecules per linker and n is an average of the number of drug-linker conjugates per BINDER. The sum of all WS present in a conjugate molecule is thus the product of m and n.
  • Linkage site with the drug characterizes, and R 22 is COOH, COOR, COR (with R each is Cl-3-alkyl), CONH2, Br, preferably COOH.
  • the linkage with the sulfur atom of the binder can thus have one of the following structures:
  • both structures according to the formulas AI and / or A2 may be present in an antibody-drug conjugate. Since the antibody-active substance conjugates according to the invention are a mixture of different antibody active substance Conjugates, it is also possible that in this mixture antibody-drug conjugates with both the formula AI or formula A2 and with the formula AI and A2 are included.
  • X represents a 5- or 6-membered, aromatic or non-aromatic heterocycle or homocycle, preferably -C5H4- or -
  • RS represents an acid group, preferably -COOH or SO 3 H, selected from -CONH-, -OCONH-, -NHCO-, -NHCOO-, where r is 1, 2 or 3.
  • L7 is a single bond or a group selected from a straight-chain or branched hydrocarbon chain having 1 to 100 (preferably 1 to 10) carbon atoms of arylene groups and / or straight-chain and / or branched and / or cyclic alkylene groups which is mono- or polysubstituted by one or more of the groups -O-, -S-, -SO-, SO 2 , -NRY-, -
  • NRYCO- -C (NH) NRy-, -CONRY-, -NRYNRY-, -SO 2 NRYNRy-, -CONRYNRY-, (wherein R y is H, phenyl, C i -Ci -Q-alkyl, C 2 -C 10 -Q alkenyl, or C2-Ci represents Q-alkynyl, each with
  • S02- may be interrupted (preferably ⁇ /), the
  • Hydrocarbon chain including side chains, if any, with -NHCONH2, -
  • L ⁇ is preferably a group selected from -CONH- and -NHCO-.
  • Li is preferably a single bond or - [(CH 2) x - (X 4 ) y ] w - (CFi 2) z-,
  • z 1 to 5; and represents.
  • reaction of A 'to A is carried out by stirring in a pH buffer having a pH of 7.5 to 8.5, preferably 8, at a temperature below 37 ° C, preferably 10 to 25 ° C, over a period of up to 40 hours, preferably 1 to 15 hours.
  • R2, R4 and R5 represent H
  • R3 represents -CH20H
  • R1 represents -L1-L2-BINDER
  • # 1 denotes the point of attachment to the sulfur atom of the antibody
  • # 2 denotes the point of attachment to the group L 1
  • R 22 is COOH, COOR, COR, CONHR (each R is Cl-3-alkyl), CONH 2 , preferably COOH.
  • the bonds to a cysteine residue of the antibody are preferably more than 80%, more preferably more than 90% (in each case based on the total number of links of the linker to the antibody), particularly preferably in one of the two structures of the formula A5 or A6 before:
  • the structures of the formula A5 or A6 are generally present together, preferably in a ratio of 60:40 to 40:60, based on the number of bonds to the antibody. The remaining bonds are then in the structure
  • the antibody is preferably an anti-TWEAKR antibody that specifically binds to amino acid D at position 47 (D47) of TWEAKR (SEQ ID NO: 169), especially anti-TWEAKR antibody TPP-2658.
  • Antibody conjugates according to any one of the following formulas are provided, wherein n is a number from 1 to 20 and AKl or AK2 are an antibody. AK1 represents an antibody linked by cysteine, AK2 an antibody linked by lysine.
  • the hyperproliferative diseases for the treatment of which the compounds according to the invention can be used include, in particular, the group of cancer and tumor diseases.
  • these are understood as meaning, but are not limited to, breast carcinomas and breast tumors (mammary carcinomas including ductal and lobular forms, also in situ), respiratory tumors (small cell and non-small cell carcinoma, Brain tumors (eg of the brainstem and hypothalamus, astrocytoma, ependymoma, glioblastoma, gliomas, medulloblastoma, meningiomas and neuro-ectodermal and pineal tumors), tumors of the digestive organs (esophageal, gastric, gallbladder, small intestine, large intestine).
  • liver tumors including hepatocellular carcinoma, cholangiocarcinoma and mixed hepatocellular cholangiocarcinoma
  • tumors of the head and neck (laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal, lip and oral carcinomas, oral melanoma)
  • Skin tumors basaliomas, spinaliomas, squamous cell carcinomas, Kaposi's sarcoma, malignant melanomas, non-melanomarti skin cancer, Merkel cell skin cancer, mast cell tumors
  • tumors of the supporting and connective tissue including soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, chondrosarcomas, fibrosarcomas, hemangiosarcomas, leiomyosarcomas, liposarcomas, lymphosarcoma).
  • tumors of the eyes including intraocular melanoma and retinoblastoma
  • tumors of the endocrine and exocrine glands eg thyroid and parathyroid glands, pancreatic and salivary gland carcinomas, adenocarcinomas
  • tumors of the urinary tract bladedder, penis, Kidney, renal pelvis and ureteral tumors
  • tumors of the reproductive organs endometrial, cervical, ovarian, vaginal, vulvar and uterine carcinomas of the woman as well as prostate and testicular carcinomas of the man.
  • proliferative disorders of the blood, lymphatic system and spinal cord in solid form and as circulating cells, such as leukemia, lymphoma and myeloproliferative disorders, eg acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myelogenous and hairy cell leukemia, as well AIDS-correlated lymphomas, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma and lymphoma in the central nervous system.
  • the treatment of the aforementioned cancers by means of the compounds according to the invention comprises both a treatment of the solid tumors and a treatment of metastatic or circulating forms thereof.
  • treatment or “treating” is used conventionally within the context of this invention and means the care, care and supervision of a patient with the aim of combating, reducing, alleviating or alleviating a disease or health deviation and improving living conditions that are affected by this disease, such as cancer.
  • Another object of the present invention is thus the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects.
  • Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
  • the compounds of the present invention may be combined with known anti-hyperproliferative, cytostatic or cytotoxic agents for the treatment of cancers.
  • suitable combination active ingredients are:
  • the compounds of the present invention can be combined, for example, with binders which can exemplarily bind to the following targets: OX-40, CD137 / 4-1BB, DR3, ID01 / ID02, LAG-3, CD40.
  • the compounds according to the invention can also be used in combination with radiotherapy and / or surgical intervention.
  • the combination of compounds of the present invention with other cytostatic or cytotoxic agents can achieve the following objectives: improved efficacy in slowing down the growth of a tumor, reducing its size or even eliminating it completely compared to a single drug treatment; the possibility to use the chemotherapeutic agents used in lower doses than in monotherapy; the possibility of a more tolerable therapy with fewer side effects compared to the single dose; the ability to treat a wider range of tumor diseases; achieving a higher response rate to the therapy; a longer survival time of patients compared to today's standard therapy.
  • the compounds according to the invention can also be used in combination with radiotherapy and / or surgical intervention.
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally. For this purpose, they can be applied in a suitable manner, such as, for example, parenterally, possibly by inhalation or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • Parenteral administration can be carried out bypassing a resorption step (eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or with involvement of resorption (eg intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions or lyophilisates.
  • Preference is given to parenteral administration, in particular intravenous administration.
  • parenteral administration amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg kg body weight to achieve effective results.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Peptides Or Proteins (AREA)
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Abstract

L'invention concerne la production de substances qui, après avoir été administrées à faible concentration, présentent une action apoptotique et peuvent ainsi être utiles en oncothérapie. Pour atteindre cet objectif, l'invention a pour objet la production de conjugués d'un anticorps aglycosyl-anti-TWEAKR ou aglycosylés avec des inhibiteurs de la KSP de formule (I), un ou plusieurs composants de la formule (I) étant lié(s) à l'anticorps au moyen d'un segment de liaison L. Les anticorps aglycosylés sont des anticorps qui ne présentent aucun glycane sur le site de liaison N conservé dans le domaine CH2 de la région Fc. L'anticorps est de préférence un anticorps monoclonal humain, humanisé ou chimérique. On préfère en particulier un anticorps anti-TWEAKR qui se lie spécifiquement à l'acide aminé D en position 47 (D47) du récepteur TWEAK (TWEAKR) (SEQ ID NO:169), en particulier l'anticorps anti-TWEAKR TPP-2658.
EP15816395.6A 2014-12-15 2015-12-10 Conjugués anticorps-principe actif (adc) d'inhibiteurs de la ksp ayant des anticorps anti-tweakr aglycosylés Pending EP3233127A1 (fr)

Applications Claiming Priority (3)

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EP14197999 2014-12-15
EP15172051 2015-06-15
PCT/EP2015/079273 WO2016096610A1 (fr) 2014-12-15 2015-12-10 Conjugués anticorps-principe actif (adc) d'inhibiteurs de la ksp ayant des anticorps anti-tweakr aglycosylés

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JP (1) JP6743015B2 (fr)
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WO (1) WO2016096610A1 (fr)

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US10485880B2 (en) 2019-11-26
CA2970565A1 (fr) 2016-06-23
US20180015176A1 (en) 2018-01-18
CN107635586A (zh) 2018-01-26
CN107635586B (zh) 2021-09-24
JP6743015B2 (ja) 2020-08-19
JP2018502844A (ja) 2018-02-01
WO2016096610A1 (fr) 2016-06-23

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