EP3313522A1 - Conjugués anticorps-principe actif (adc) d'inhibiteurs de ksp avec des anticorps anti-b7h3 - Google Patents

Conjugués anticorps-principe actif (adc) d'inhibiteurs de ksp avec des anticorps anti-b7h3

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Publication number
EP3313522A1
EP3313522A1 EP16733024.0A EP16733024A EP3313522A1 EP 3313522 A1 EP3313522 A1 EP 3313522A1 EP 16733024 A EP16733024 A EP 16733024A EP 3313522 A1 EP3313522 A1 EP 3313522A1
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EP
European Patent Office
Prior art keywords
alkyl
cooh
seq
represented
bhc
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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EP16733024.0A
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German (de)
English (en)
Inventor
Hans-Georg Lerchen
Anne-Sophie Rebstock
Yolanda Cancho Grande
Sven WITTROCK
Sandra Berndt
Uwe Gritzan
Jenny FITTING
Beatrix Stelte-Ludwig
Patrick Jones
Christoph Mahlert
Christian Votsmeier
Dorian SCHÖNFELD
Mark Trautwein
Ernst Weber
Nikolaus Pawlowski
Simone Greven
Julian Marius GLÜCK
Stefanie Hammer
Lisa Dietz
Stephan MÄRSCH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
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Bayer Pharma AG
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Publication date
Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Publication of EP3313522A1 publication Critical patent/EP3313522A1/fr
Pending legal-status Critical Current

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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
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6865—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from skin, nerves or brain cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—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 receptor, a cell surface antigen or a cell surface determinant
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
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    • 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
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    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6857—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from lung cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6863—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from stomach or intestines cancer cell
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • 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

Definitions

  • ADCs Antibody-drug conjugates
  • 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 to a significantly lower limit than conventional chemotherapy for cancer [see, eg, JM Lambert, Curr. Opin. Pharmacol., 5, 543-549 BHC 15 1 040-A
  • 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 KJF11) 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 a glycosylated or aglycosylated-anti-B7H3 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 are.
  • aglycosylated antibodies have no glycans at the conserved N-binding site in the CH2 domain of the Fc region and therefore do not bind to NK cells. Therefore, an aglycosylated antibody does not support NK cell-mediated cellular cytotoxicity.
  • the antibody is preferably a human, humanized or chimeric monoclonal antibody.
  • anti-B7H3 antibodies which specifically bind the human Ig4 and / or the human and / or murine Ig2 isoform of B7H3, in particular BHC 15 1 040-A the anti-B7H3 antibodies TPP-6497, TTP-6499, TPP-6501, TPP-6502, TPP-6515, TPP-7611, TPP-8382, TPP-8564, TPP-8567, TPP- 8322, TPP-8565, TPP-8568, TPP-8748 and TPP-8750.
  • 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'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 ) 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 , Ci- ⁇ 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 is -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY'Y 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 -
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 , Ci- ⁇ 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 G_6 is alkyl;
  • R 4 H, L # 1, -SG lys - (CO) 0 . 1 represents -R 4 ', -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • SG j y g is a group cleavable by a lysosomal enzyme, in particular a group consisting of a di- or tripeptide
  • R 4 ' is an O-io-alkyl, Cs-io-aryl or Ce- ⁇ o- aralkyl-, Cs io-heteroalkyl, C 1-10 -alkyl-O-C6-io-aryl, Cs-io-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkoxy, G-io-alkoxy, C6-io Aryloxy or C0-io-aralkoxy, C5-10-heteroaralkoxy, Ci-io-alkyl-O-Cö-io-aryloxy, Cs io-heterocycloalkoxy group which is one or more times with - NH 2 , -NH Alkyl, -N (alkyl)
  • Y 1 and Y 2 independently represent H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 represents H or - (CH 2 ) o- 3 Z', wherein Z 'is H, SO 3 H, NH 2 or COOH;
  • Y 4 is linear or branched, optionally with -NHCONH 2 substituted, C1-5 alkyl or optionally substituted with -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y 6 linear or branched G_6 is alkyl;
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR n - or -CHR n -CH 2 -, wherein R 11 is H, NH 2 , SO 3 H, COOH, SH, halogen (especially F or Cl), C i alkyl, C i i- 4 alkyl, COO (Ci represents ⁇ haloalkyl, Ci- 4 alkoxy, hydroxyl-substituted C 4 alkyl), or OH;
  • A represents CO, SO, S0 2 , S0 2 NH or CNNH 2 ;
  • R 3 represents -L- # 1, -MOD, or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably -L- # 1 or a G-10-alkyl, C6 -10- aryl or C0-io-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-0-C6-io-aryl or C5-10-heterocycloalkyl group, which 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 G-io-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 ) o- 3 Z is where Z is -H, -OY 3 , -SY 3 , halogen, NHY 3 , -CO-NY'Y 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 ) o- 3 Z', where Z 'is H, SO 3 H Represents 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-10-alkyl, (optionally fluorinated) C 2-10 -alkenyl, (optionally fluorinated) C 2-10 -alkynyl, (optionally fluorinated) C 1-4 -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 - (GI) o -G 2 -G 3 wherein R 10 represents H or C 1 -C 3 alkyl;
  • 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 1 g-alkyl, C 2 -C 1 g Alkenyl, or C2-C represents 1 g-alkynyl, 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 cleavable by a protease linker.
  • 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.
  • the invention provides novel low molecular weight KSP inhibitors which are conjugated to an anti-B7H3 antibody.
  • KSP inhibitors or their antibody conjugates have the following general formula (II):
  • R 1 represents H, -L-BINDER, -MOD or - (CH 2 ) 0 - 3 Z, where Z is -H, -NHY 3 , -
  • Y 1 and Y 2 independently of one another are H, NH 2 , - (CH 2 CH 2 O) 3 - (CH 2 ) o-3Z '(for example,
  • Y 3 represents H or - (CH 2 ) 0 - 3 Z '
  • W represents H or OH
  • G_6 is alkyl or optionally substituted by -NH 2 substituted aryl or benzyl;
  • R 2 and R 4 together (to form a pyrrolidine ring) -CH 2 -CHR n - or
  • R 11 is -H, -NH 2 , -SO 3 H, -COOH, -SH, halogen (in particular F or Cl),
  • Z is halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY'Y 2 , or -CO-
  • OY 3 represents,
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is H or - (CH 2 ) o- 3 Z', where Z 'is H, SO 3 H, NH 2 or COOH represents;
  • Y 4 represents linear or branched, optionally with NHCONH 2 substituted, G-6 alkyl or optionally substituted with -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y 6 linear or branched G-6 is alkyl;
  • R 4 H, -L-BINDER, -SG lys - (CO) 0 . 1 represents -R 4 ', -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • SG j y g is a group cleavable by a lysosomal enzyme, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a G-io-alkyl, G-io-aryl or G-io-aralkyl-, G-io-heteroalkyl, Ci-io-alkyl-0-C6-io-aryl, G-io-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkoxy, Ci-io-alkoxy, G -io-aryloxy or G-io-aralkoxy, G-io-heteroaralkoxy, G-io-alkyl-OG-io-aryloxy, G-10-heterocycloalkoxy group which is mono- or polysubstituted with - NH 2 , -NH-alkyl, -N (alkyl) 2
  • Z is -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) 0 -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 G-6 is alkyl;
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR n - or -CHR n -CH 2 -, wherein R 11 is H, NH 2 , SO 3 H, COOH, SH, halogen (especially F or Cl), C i alkyl, C i i- 4 alkyl, COO (G- represents ⁇ haloalkyl, Ci- 4 alkoxy, hydroxyl-substituted C 4 alkyl), or OH;
  • R 3 represents -L-BINDER, -MOD, or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably -L-BINDER or a G-10-alkyl, C 10 -o -Aryl or G-io-aralkyl, G-10-heteroalkyl, G-io-alkyl-OG-io-aryl or C 5-10 -heterocycloalkyl group which are substituted by 1 -3 -OH groups, 3 halogen atoms, 1 -3 halogenated BHC 15 1 040-A - 10 -
  • 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) n -alkyl groups, 1-3 - S0 2 -NH-alkyl groups, 1-3 -NH-alkyl groups, 1-3 -N (alkyl) 2 groups, 1-3 -NH 2 groups or 1-3 - (CH 2 ) 0 - 3 Z groups, wherein Z is -H, halogen, -OY 3 , -SY 3 , -NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 , with Y 1 and Y 2 independently of one another H, NH 2 , or -
  • alkyl is preferably G-10-alkyl
  • n 0, 1 or 2
  • 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 where Z is -H, -OY 3 , -SY 3 , halogen, NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 , where Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2) 0 - 3.
  • R 8 (optionally fluorinated) C-10-alkyl, (optionally fluorinated) C 2 _io-alkenyl, (optionally fluorinated) C 2 -io-alkynyl, (optionally fluorinated) C 4 -o-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-B7H3 antibody, wherein the binder may optionally be bound to a plurality of drug molecules, wherein a member of R 1 is R 3 , and R 4 is -L-Binder;
  • R 6 and R 7 are independently H, cyano, (optionally fluorinated) C1-10- alkyl, (optionally fluorinated) C2-10- alkenyl, (optionally fluorinated) C2 -io-alkynyl, hydroxy, N0 2, NH 2 , COOH or halogen (especially F, Cl, Br), wherein -MOD represents - (NR 10 ) n - (GI) o -G 2 -G 3 wherein R 10 represents H or GC 3 alkyl;
  • n 0 or 1;
  • BHC 15 1 040-A - 11 - o is 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, Ci-Ci-alkyl, C2-C1 g Alkenyl, or C2-C1 represents g-alkynyl, each with
  • FIG. 1 Internalization behavior of specific B7H3 antibodies in the human renal cancer cell line A498.
  • the invention provides conjugates of an anti-B7H3 antibody as well as aglycosylated and / or humanized variants thereof 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
  • n where BINDER stands for the anti-B7H3 antibody, L for the linker, KSP for the KSP inhibitor, and 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 antibody is preferably a human, humanized or chimeric anti-B 7H3 monoclonal antibody or antigen-binding fragment thereof.
  • anti-B7H3 antibodies which specifically bind the human 4Ig isoform, in particular the human anti-B7H3 antibodies TPP-6497, TTP-6499, TPP-6501, TPP-6502, TPP-6515.
  • the anti-B 7H3 antibody or the antigen-binding fragment is aglycosylated.
  • 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.
  • substituted means that one or more hydrogens on the designated atom or group are replaced by a selection from the group indicated, provided that the normal valence of the designated atom has not been exceeded under the present circumstances Combinations of substituents and / or variables are permitted.
  • optionally substituted means that the number of substituents may be the same or different from 0. Unless otherwise indicated, optionally substituted groups may be substituted by as many optional substituents as may be substituted by replacement of a hydrogen by a non-hydrogen substituent. Typically, the number of optional substituents (if present) may be 1, 2, 3, 4 or 5, more preferably 1, 2 or 3.
  • the term "one or more times", for example, in the definition of the substituents of the compounds of the general formulas of the present invention, means "1, 2, 3, 4 or 5, preferably 1, 2, 3 or 4, more preferably 1, 2 or 3, most preferably 1 or 2 ".
  • radicals are substituted in the compounds according to the invention, the radicals can, unless stated otherwise, be monosubstituted or polysubstituted.
  • the meanings of all residues that occur multiple times are independent of each other. Substitution by one, two or three identical or different substituents is preferred. Substitution by a substituent is particularly preferred.
  • Alkyl is a linear or branched, saturated, monovalent hydrocarbon radical having 1 to 10 carbon atoms (G-Go-alkyl), generally 1 to 6 (GG-alkyl), preferably 1 to 4 (G-G-alkyl), and particularly preferably 1 to 3 carbon atoms (GG-alkyl).
  • Particularly preferred is a methyl, ethyl, propyl, isopropyl and tert-butyl radical.
  • Sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted.
  • R x is -H, C 1 -C 3 -alkyl or phenyl.
  • Alkenyl is a straight-chain or branched monovalent hydrocarbon chain having one or two double bonds and 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (C 2 -C 10 alkenyl), in particular 2 or 3 carbon atoms (C2 -C 3 alkenyl), it being understood that when the alkenyl group contains more than one double bond, the double bonds may be isolated from each other or conjugated with each other.
  • the alkenyl group is, for example, an ethenyl (or vinyl), prop-2-en-1-yl (or “allyl”), prop-1-en-1-yl, but 3-enyl, but-2-enyl, but-1-enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1-enyl, hexane 5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1-enyl, prop-1-en-2-yl (or "isopropenyl") )
  • the group is vinyl or allyl.
  • Alkynyl represents a straight-chain or branched monovalent hydrocarbon chain having one triple bond and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (C 2 -C 10 -alkynyl), in particular 2 or 3 carbon atoms (C 2 -C 3 ) alkynyl).
  • the C 2 -C 6 alkynyl group is, for example, an ethynyl, prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-one inyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl , Hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl,
  • alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
  • Cycloalkyl is a saturated monovalent mono- or bicyclic hydrocarbon radical having 3-12 carbon atoms (C 3 -C 2 -cycloalkyl).
  • a mono cvclis is more likely to be carbon which is first free for a monovalent one
  • Hydrocarbon radical having generally 3 to 10 (C 3 -Cio-cycloalkyl), preferably 3 to 8 (C 3 -C 8 -cycloalkyl), and particularly preferably 3 to 7 (C 3 -C 7 -cycloalkyl) carbon atoms.
  • C 3 -Cio-cycloalkyl preferably 3 to 8 (C 3 -C 8 -cycloalkyl), and particularly preferably 3 to 7 (C 3 -C 7 -cycloalkyl) carbon atoms.
  • a monocyclic hydrocarbon radical mention may be made:
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl and
  • hydrocarbon radical of a hydrocarbon radical having usually 3 to 12 carbon atoms C3-Ci2 cycloalkyl
  • a fusion of two saturated ring systems is to be understood, commonly shared by two directly adjacent atoms.
  • bicyclic hydrocarbon radical bicyclo [2.2.0] hexyl, bicyclo [3.3.0] octyl, bicyclo [4.4.0] decyl, bicyclo [5.4.0] undecyl, bicyclo [3.2.
  • Heterocycloalkyl is a non-aromatic mono- or bicyclic ring system having one, two, three or four heteroatoms, which may be the same or different. As heteroatoms nitrogen atoms, oxygen atoms or sulfur atoms can occur.
  • a monocyclic ring system according to the present invention may have 3 to 8, preferably 4 to 7, more preferably 5 or 6 ring atoms.
  • heterocycloalkyl having 4 ring atoms examples and preferred for a heterocycloalkyl having 4 ring atoms are:
  • heterocycloalkyl having 7 ring atoms examples and preferred for a heterocycloalkyl having 7 ring atoms are:
  • Azepanyl, oxepanyl, 1,3-diazepanyl, 1, 4-diazepanyl is azepanyl, oxepanyl, 1,3-diazepanyl, 1, 4-diazepanyl.
  • heterocycloalkyl having 8 ring atoms examples and preferred for a heterocycloalkyl having 8 ring atoms are:
  • Oxocanyl, azocanyl
  • saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S are preferred.
  • a bicyclic ring system having one, two, three or four heteroatoms, which may be the same or different, may according to the present invention have from 6 to 12, preferably 6 to 10 ring atoms, with one, two, three or four carbon atoms against the same or different heteroatoms from the series O, N and S can be exchanged.
  • Examples include: azabicyclo [3.3.0] octyl, azabicyclo [4.3.0] nonyl,
  • Aryl is a monovalent, mono- or bicyclic, aromatic carbon ring system consisting of carbon atoms. Examples are naphthyl and phenyl; preferred is phenyl or a phenyl radical.
  • C 10 -alkyl-aralkyl represents a monocyclic aromatic aryl, exemplified by phenyl, to which a G-C 4 -alkyl group is attached.
  • An exemplary C 10 -o-aralkyl group is benzyl.
  • Heteroaryl means a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl" group), especially 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the group consisting of N, O and S and which is bonded via a ring carbon atom or optionally (if it allows the valency) via a ring nitrogen atom.
  • the heteroaryl group may be a 5-membered heteroaryl group such as thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group such as carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, ind
  • heteroaryl radicals include all possible isomeric forms thereof, e.g. Tautomers and positional isomers with respect to
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • C5-io-heteroaryl in the context of the invention represents a mono- or bicyclic, aromatic ring system having one, two, three or four heteroatoms, which may be identical or different.
  • the bond valency may be at any aromatic carbon atom or at a nitrogen atom.
  • a monocyclic heteroaryl group according to the present invention has 5 or 6 ring atoms. Preference is given to those heteroaryl radicals having one or two heteroatoms. Particularly preferred are one or two nitrogen atoms.
  • heteroaryl radicals having 5 ring atoms include the rings:
  • Heteroaryl radicals having 6 ring atoms include, for example, the rings:
  • a bicyclic heteroaryl group according to the present invention has 9 or 10 ring atoms.
  • heteroaryl radicals having 9 ring atoms include the rings:
  • Benzothienyl Benzimidazolyl, benzoxazolyl, azocinyl, indolizinyl, purinyl, indolinyl.
  • Heteroaryl radicals with 10 ring atoms include, for example, the rings:
  • Sulfone, sulfoxide, or sulfonic acid may be substituted, BHC 15 1 040-A - 20 -
  • Sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted.
  • R x is -H, C 1 -C 3 -alkyl or phenyl.
  • Halogen or halogen atom in the context of the invention is fluorine (-F), chlorine (-C1), bromine (-Br), or iodine (-1).
  • Fluoroalkyl, fluoroalkenyl and fluoroalkynyl mean that the alkyl, alkenyl and alkynyl may be substituted one or more times by fluorine.
  • 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'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 ) 0 - 3 Z'), or -CH (CH 3 ) 2 2 W) represent 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 , G_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 is -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 ) 0 - 3 Z ', and Y 3 is H or -
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 , Ci-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 G_6 is alkyl;
  • -SG lys - (CO) 0 . 1 represents -R 4 ', -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • SG j y g represents a group cleavable by a lysosomal enzyme, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a G-io-alkyl, Cs-io-aryl or C ⁇ -IO aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-0-C6-io-aryl, Cs-io-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkoxy, Ci-io-alkoxy, Cö -io-aryloxy or C10-aroalkoxy, C 5-10 heteroaralkoxy, C 1-10 -alkyl-O-C0-io-aryloxy, C 1-10 -heterocycloalkoxy group which is mono- or polysubstituted with --NH 2 , -NH-alkyl, -N (alkyl) 2
  • Z is -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 ) 0 - 3 Z ', 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;
  • BHC 15 1 040-A - 22 - or R 2 and R 4 together (to form a pyrrolidine ring) represent -CH 2 -CHR 11 - or -CHR n -CH 2 -, wherein R 11 is H, NH 2 , SO 3 H, COOH, SH , halogen (especially F or Cl), C i alkyl, haloalkyl, Ci- 4 alkoxy, hydroxyl-substituted G 4 alkyl, COO (CI-4 alkyl) or OH;
  • A represents CO, SO, SO 2 , SO 2 NH or CNNH 2 ;
  • R 3 represents -L- # 1, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably a C 1-10 -alkyl, C 6-10 aryl or Ce- 10-aralkyl, C5-io-heteroalkyl, Ci-io-alkyl-O-Cö-io-aryl or Cs-io-heterocycloalkyl group, which 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 -
  • 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) n -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) 1 .2oH) groups, 1 -3 -NH 2 groups or
  • 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'Y 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 ) o- 3 Z', where Z 'is H, SO 3 H, NH 2 or COOH;
  • R 6 and R 7 independently of one another are H, cyano, (optionally fluorinated) C 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) represent,
  • R 8 (optionally fluorinated) C-10-alkyl, (optionally fluorinated) C 2 -alkenyl, (optionally fluorinated) C 2 -alkynyl, (optionally fluorinated) C 4 -iodo-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, BHC 15 1 040-A - 23 -
  • L is the linker and # 1 is the bond to the antibody
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2
  • -MOD - represents (NR 10 ) n - (GI) o -G 2 -G 3 wherein R 10 represents H or C 1 -C 3 alkyl
  • 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, Ci-Ci-alkyl, C2-C1 g Alkenyl, or C2-C1 represents g-alkynyl, each with
  • NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid), -CO-, or -CR x N-O- (where Rx H, C 1 -C 3 -alkyl or phenyl), wherein the hydrocarbon chain including the side chains, if present, with -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone, sulfoxide, or Sulfonic acid may be substituted, wherein G3 is -H or COOH, and wherein the group -MOD preferably has at least one group -COOH; and their salts, solvates, salts of solvates and epimers.
  • one of the substituents R 1 or R 3 -L represents # 1 in this embodiment it is particularly preferred if R 4 is H or -SG j y S -. (CO) O_i-R 4 ', where SG jys and R 4 ' have the same meaning as above.
  • R 1 When R 1 is not H, the carbon atom to which R 1 binds is a stereocenter which may be in the L and / or D configuration, preferably in the L configuration.
  • R 2 is not H
  • the carbon atom to which R 2 binds is a stereocenter which may be in the L and / or D configuration.
  • R 1 is H, -L- # 1, or - (CH 2 ) 0 - 3 Z, wherein Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY'Y 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-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; wherein represents WH or OH;
  • Y 4 is linear or branched, optionally substituted with-NHCONH 2 , Ci- ⁇ alkyl or optionally substituted with -NH 2 substituted aryl or benzyl.
  • R 2 and R 4 are independently H
  • -SG lys - (CO) 0 . 1 represents -R 4 ', -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • SG j y g is a group cleavable by a lysosomal enzyme, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a G-io-alkyl, Cs-io-aryl or Ce- ⁇ o- aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-0-C6-io-aryl, Cs-io-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkoxy, G-io-alkoxy, C6 -io-aryloxy or C6-io-aralkoxy, C5-10-heteroaralkoxy, Ci-io-alkyl-O-Cö-io-aryloxy, Cs io-heterocycloalkoxy group, each one or more times with - NH 2 , -NH-alkyl, -N (al
  • 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), G 4 alkyl, C1-4 haloalkyl, G 4 represents alkoxy, hydroxyl-substituted G 4 alkyl, COO (C w alkyl), or OH; or R 2 is H, -CO-CHY 4 -NHY 5 or - (CH 2 ) o- 3 Z and R 4 is -L- # 1 wherein Z is - H, halo, -OY 3 , -SY 3 , NHY 3 represents -CO-NY'Y 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, SO 3 H, NH 2 or COOH;
  • Y 4 is independently linear or branched, optionally substituted with -NHCONH2, C 1-6 alkyl or optionally substituted with -NH 2 substituted aryl or benzyl, wherein Y 4 linear or branched, optionally substituted with -NHCONH 2 , C 1-6 represents alkyl or optionally substituted aryl with NH2 or benzyl and Y is H 5 or -CO-CHY 6 -NH 2, where Y represents 6 linear or branched alkyl G_6;
  • A represents CO, SO, SO 2 , SO 2 NH or CNNH 2 ;
  • R 3 represents an optionally substituted alkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably -L-# 1 or a G-10-alkyl, cyclo-aryl or cyclo-aralkyl-, C 5-10 heteroalkyl, C 1-10 -alkyl-O-C0 -10-aryl or C 1-10 -heterocycloalkyl groups which have 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-alkyl groups, 1-3 -NH-CO-NH-alkyl groups, 1-3 -S
  • alkyl is preferably G- 10- alkyl
  • R 5 is H, F, NH 2 , NO 2 , halogen, SH or - (CH 2 ) o- 3 Z, where Z is -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY ' Y 2 represents 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 ) o-3Z', where Z 'is H, SO 3 H, NH 2 or COOH; BHC 15 1 040-A - 26 -
  • 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 or halogen,
  • R 8 represents (optionally fluorinated) G-10-alkyl, (optionally fluorinated) C 4 -o cyclo-cyclo or optionally substituted oxetane;
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; and their salts, solvates, salts of solvates and epimers.
  • 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.
  • one of the substituents R 1 or R 3 -L represents # l in this embodiment it is particularly preferred if R 4 is H or -SG j y S -.
  • the binder is preferably a human, humanized or chimeric monoclonal antibody or antigen-binding fragment thereof.
  • anti-B7H3 antibodies which specifically bind the human Ig4 and / or the human and / or murine Ig2 isoform of B7H3, in particular the anti-B7H3 antibodies TPP-6497, TTP-6499, TPP-6501, TPP-6502, TPP-6515.
  • the anti-B7H3 antibody is present in aglycosylation.
  • 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 can BHC 15 1040-A-27 naturally present in the protein, can be introduced by biochemical methods or can preferably be generated by prior reduction of disulfides of the binder.
  • CO carbonyl
  • R 1 is preferably -L- # l, H, -COOH, -CONHNH2, - (CH 2 ) i- 3 NH 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 n -CH 2 -, wherein R 11 is H or F.
  • R 4 is -L- # 1, where -L- # 1 is a cleavable linker, preferably an intracellular enzymatically cleavable linker.
  • R 3 is preferably -L- # l or a C 1-10 -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) n -alkyl, S0 2 -NH-alkyl, NH-alkyl, N (alkyl) 2 , or NH 2 may be substituted (wherein alkyl is preferably C1-3 alkyl).
  • R 5 is preferably H or F.
  • R 6 and R 7 are independently of each other preferably H, (optionally fluorinated) ⁇ -3-alkyl, (optionally fluorinated) C 2 ⁇ -alkenyl, (optionally fluorinated) C 2 -4-alkynyl, hydroxy or halogen.
  • R 8 is preferably a branched ⁇ -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.
  • 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 is 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 n - or -CHR n -CH 2 -, wherein R 11 represents H; or R 4 is -L- # 1 and R 2 is H; BHC 15 1 040-A - 28 -
  • 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 ) n -alkyl, S0 2 -NH-alkyl, NH-alkyl, N (alkyl) 2 , or NH 2 may be substituted (wherein alkyl is preferably C1-3 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 n - or -CHR n -CH 2 -, where R 11 is H, or R 4 -L- # l is and R 2 is H;
  • A represents CO
  • R represents 5 or H
  • R 6 and R 7 independently of one another are H, G- 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. BHC 15 1 040-A - 29 -
  • R 1 represents -L- # 1, COOH or H
  • 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 n -CH 2 -, where R 11 is H,
  • A represents CO
  • R 5 represents H
  • R 6 and R 7 independently of one another are H, G- 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 ) 0 - 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY'Y 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 are independently H, NH 2, - (CH 2 CH 2 O) 0-3 - (CH 2) 0 - 3.
  • Z'), or - Z is CH (CH 2 W) 'represent, and Y 3 is H or - (CH 2) 0 - 3.
  • Z' group wherein Z 'is H, NH 2, S0 3 H, - COOH, -NH-CO-CH 2 - CH 2 is -CH (NH 2 ) COOH or - (CO-NH-CHY 4 ) i- 3 COOH; where represents WH or OH, BHC 15 1040-A - wherein Y 4 is linear or branched, optionally substituted with-NHCONH2, Ci- ⁇ alkyl or optionally -NH 2 substituted aryl or benzyl;
  • R 2 is H, -MOD, -CO-CHY 4 -NHY 5 or - (CH 2 ) o- 3 Z, wherein Y 4 is linear or branched, optionally substituted with-NHCONH 2 , Ci- ⁇ alkyl or optionally with -NH 2 represents substituted aryl or benzyl and Y 5 represents H or -CO-CHY 6 -NH 2 , wherein Y 6 represents linear or branched Ci- ⁇ alkyl,
  • Z is -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) 0 -3Z ', and Y 3 is H or -
  • SG j y S is a group cleavable by lysosomal enzymes, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a C 0 -alkyl, C 5-10 -aryl or -glyo-aralkyl-, C 5- 10- heteroalkyl, G-io-alkyl-OG-io-aryl, G-10-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkoxy, Ci-10-alkoxy, G-io-aryloxy - or C6-io-aralkoxy, G-10-heteroaralkoxy, G-io-alkyl-0-C6-io-aryloxy, G-10-heterocycloalkoxy group, one or more times with -NH 2 , -NH - alkyl, -N (alkyl) 2 , NH-CO-alkyl, N (alkyl
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) 0 -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 , where Y 6 linear or branched G_6 is alkyl;
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR n - or -CHR n -CH 2 -, wherein R 11 is H, NH 2 , SO 3 H, COOH, SH, halogen (especially F or Cl), G ⁇ alkyl, G- 4 haloalkyl, G-4Alkoxy, hydroxyl-substituted G ⁇ alkyl, COO (C 1-4 alkyl) or OH;
  • A represents CO, SO, S0 2 , S0 2 NH or CNNH 2 ;
  • R 3 is -L-Binder, -MOD, or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably -L-BINDER or a G-10-alkyl-, BHC 15 1 040-A - 31 -
  • C 10 -o-aryl or C 10 -o-aralkyl C 1-10 -heteroalkyl, C 1-10 -alkyl-O-C0 -10-aryl or C 5-10 -heterocycloalkyl groups which are 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 -NH-CO-NH-alkyl groups, 1-3 -S ( 0) n -alkyl groups, 1-3 -SO 2 -NH-alkyl groups, 1-3 -NH-alkyl groups, 1-3 -N (alkyl) 2 groups, 1-3 -NH 2 groups or 1-3
  • alkyl is preferably G- 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 where Z is -H, -OY 3 , -SY 3 , halogen, NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 , where Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', wherein Z 'represents H, SO 3 H, NH 2 or COOH;
  • R 6 and R 7 are each independently H, cyano, (optionally fluorinated) C O-alkyl, (optionally fluorinated) C 2-10 alkenyl, (optionally fluorinated) C 2 -io-alkynyl, hydroxy, N0 2 , NH 2 , COOH or halogen (especially F, Cl, Br),
  • R 8 (optionally fluorinated) C- 10- alkyl, (optionally fluorinated) C 2 _io-alkenyl, (optionally fluorinated) C 2 -io-alkynyl, (optionally fluorinated) C 4 -o-cycloalkyl or (CH 2) from 0 - 2 - (HZ 2), wherein HZ 2 4 to 7-membered heterocycle having up to two heteroatoms selected from N, O and S is, where each of these groups 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 -MOD - (NR 10 ) n - (GI) o -G2-G3, wherein
  • R 10 is H or GC 3 alkyl
  • n 0 or 1
  • o is 0 or 1; and BHC 15 1 040-A - 32 -
  • 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-, -
  • NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid), -CO-, or -CR x N-O- (where Rx H, C C 1 -C 3 -alkyl or phenyl), wherein the hydrocarbon chain including the side chains, if present, with -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone, sulfoxide, or Sulfonic acid may be substituted, G3 is -H or -COOH, and wherein the group - MOD preferably has at least one group -COOH; and their salts, solvates, salts of solvates and epimers.
  • 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 ) 0 - 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY'Y 2 , or - CO-OY 3 represents,
  • Y 1 and Y 2 are independently H, NH 2, - (CH 2 CH 2 O) 0 - 3 - (CH 2) 0 3 Z 'Z, or -CH (CH 2 W)', and Y 3 is 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 ) i_ 3 represents COOH; wherein represents WH or OH; BHC 15 1 040-A - 33 - wherein Y 4 is linear or branched, optionally substituted with -NHCONH 2 , Ci- ⁇ alkyl or optionally -NH 2 substituted aryl or benzyl;
  • R 2 and R 4 are independently H, -SG lys - (CO) -R i 0. 4 ', -CO-CHY 4 5 or -NHY - 3 represent Z, or R 2 and R 4 - (CH 2) 0 together represent (to form a pyrrolidine ring) -CH 2 -CHR n - or - CHR n -CH 2 -, or R 2 represents H, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z, and R 4 -L- # 1 where R 11 is H, NH 2 , SO 3 H, COOH, SH, halogen (especially F or Cl), G 4 alkyl, G 4 haloalkyl, C 1-4 alkoxy, hydroxyl-substituted cis 4 represents alkyl, COO (C 1-4 -alkyl) or OH; wherein SG j y S is a group cleavable by lysosomal
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) 0 -3Z ', and Y 3 is H or -
  • Y 4 is linear or branched, optionally substituted by-NHCONH 2 , G_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 G_6 alkyl represents;
  • A represents CO, SO, S0 2 , S0 2 NH or CNNH 2 ;
  • R 3 represents -L-BINDER or an optionally substituted alkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably -L-BINDER or a G- 10 -alkyl, C 10 -ol-aryl or C 10 -ol -Aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-O-Cö-io-aryl or Cs-io-heterocycloalkyl group, which 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 G-10-alkyl
  • R 5 is H, F, NH 2 , NO 2 , halogen, SH or - (CH 2 ) o- 3 Z, where Z is -H, halogen, -OY 3 , -SY 3 , -NHY 3 , -CO-NY ' Y 2 represents 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 ) o- 3 Z', where Z 'is H, SO 3 H, NH 2 or COOH;
  • 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,
  • R 6 and R 7 independently of one another represent H, cyano, (optionally fluorinated) C 0-alkyl, (optionally fluorinated) C 2-10 -alkenyl, (optionally fluorinated) C 2 -io-alkynyl, hydroxyl or halogen,
  • R 8 represents (optionally fluorinated) G-10-alkyl, (optionally fluorinated) C 4 -o cyclo-cyclo or optionally substituted oxetane;
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; and their salts, solvates, salts of solvates and epimers.
  • a CO B represents a single bond, -O-CH 2 - or -CH 2 -O-, and R 20 represents NH 2 , F, CF 3 , or CH 3 , and n represents 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) ⁇ M-CHY 5 -COOH, 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! Represents L-BINDER.
  • R 1 or R 3 particularly preferably represent -MOD.
  • Formula (Ilj) has: BHC 15 1 040-A - 37 -
  • 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)
  • 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 is - (CH 2 ) o- 3 Z, where Z is COOH or -CO-NY'Y 2 , where Y 2 - (CH 2 CH 2 O) 0 - 3 -
  • (CH 2 ) 0 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 2 represents -CH 2 CH 2 Z 'and Z' represents - (CONHCHY 4 ) 2 COOH;
  • Y 1 is H
  • Y 2 is -CH 2 CH 2 Z '
  • Z' is - (CONHCHY 4 ) 2 COOH and one Y 4 is z-propyl and the other is - (CH 2 ) 3 -NHCONH 2 ;
  • Y 1 represents H
  • Y 2 represents -CH 2 CH 2 Z ', Z' - (CONHCHY 4 ) 2 COOH and one Y 4 represents -CH 3 and the other represents - (CH 2 ) 3 -NHCONH 2 ;
  • Y 4 represents linear or branched, optionally substituted by -NHCONH 2 , 0_6 alkyl; at least one member of Y 4 is selected from z-propyl or -CH 3 .
  • Y 1 represents H
  • Y 2 represents -CH 2 CH 2 Z '
  • 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 Ci-6 alkyl.
  • R 1 , R 2 or R 3 in formula (I) or (II) represents -MOD
  • R 3 -MOD and R 1 or R 4 -L- # l or -L-BINDER represents wherein -MOD - (NR 10) N - (Gl) represents o-G2-G3, wherein
  • R 10 is H or C 1 -C 3 -alkyl
  • 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-, -
  • 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 is H or NHY 6 , where Y 6 is H or - COCH 3 represents.
  • R 1 represents -L-BINDER, H, or - (CH 2 ) 0 - 3 Z, wherein Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY'Y 2 , or -CO Represents -OY 3 ,
  • 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 - '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 ) i_ 3 represents COOH;
  • Y 4 is linear or branched, optionally substituted with -NHCONH 2 , G_6 alkyl or optionally substituted with -NH 2 substituted aryl or benzyl;
  • R 2 and R 4 independently of one another H, -SG lys - (CO) 0 . 1 -R 4 ', -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 n - or - CHR n -CH 2 - represent wherein R 1 1 is H, NH 2, S0 3 H, COOH, SH, halo (especially F or Cl), alkyl IA, IA haloalkyl, C ⁇ A alkoxy, hydroxyl-substituted Ci- 4 alkyl, COO (C w alkyl) or OH; BHC 15 1 040-A - 40 - wherein SG j y S is a group cleavable by lysosomal enzymes, in particular a group consisting of a di- or tripeptide, R 4 'is a G
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) 0 -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;
  • A represents CO, SO, S0 2 , S0 2 NH or CNNH 2 ;
  • R 3 -L-BESiDER an optionally substituted alkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, or -CH 2 -S x - (CH 2 ) 0 -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 .
  • alkyl is preferably G-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 Y 2 , or -CO-OY 3 , BHC 15 1 040-A - 41 - wherein Y 1 and Y 2 independently of one another represent H, NH 2 , or - (CH 2 ) o- 3 Z ', and Y 3 H or - (CH 2 ) o- 3 Z' where Z 'is H, SO 3 H, NH 2 or COOH; where L is a linker and BINDER is the antibody, where the binder may possibly be bound to several active substance molecules,
  • 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 or halogen,
  • R 8 represents (optionally fluorinated) C 1-10 -alkyl, (optionally fluorinated) C 1-4 -cycloalkyl or optionally substituted oxetane;
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; and their salts, solvates, salts of solvates and epimers.
  • Z represents Cl or Br
  • R 1 - (CH 2) o- 3 Z group wherein Z represents -CO-NY'Y 2, wherein Y 2 - (CH 2 CH 2 O) 0 - 3 - (CH 2) 3 0 Z 'and Y 1 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 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' represents - (CONHCHY 4 ) 2 COOH and represents one representative of Y 4 - CH 3 and the other represents - (CH 2 ) 3 -NHCONH 2 ;
  • Y 4 is C 1-5 alkyl, linear or branched, optionally substituted with -NHCONH 2 ; 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 ) o- 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 represents linear or branched C 1-6 alkyl optionally substituted with -NHCONH 2 .
  • 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'Y 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-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 , G_6 alkyl or optionally substituted with -NH 2 substituted aryl or benzyl;
  • R 2 represents H, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • Z is -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 ) 0 - 3 Z ', and Y 3 is H or -
  • Y 4 is independently linear or branched, optionally substituted with -NHCONH 2 , C i- ⁇ alkyl or optionally substituted with -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y is 6 linear or branched Ci-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, S0 2 , S0 2 NH or CNNH 2 ;
  • R 3 represents -L-l or -L-BINDER, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably a Ci-io-alkyl, C6 -io-aryl or C0-io-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-O-C0-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 -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
  • 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'Y 2, or -CO-OY represents 3,
  • Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 ) 0 -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-io alkyl, (optionally fluorinated) C2-10- alkenyl, (optionally fluorinated) C2 -io-alkynyl, hydroxy, N0 2, NH 2 , COOH or halogen (especially F, Cl, Br),
  • R 8 (optionally fluorinated) C- 10- alkyl, (optionally fluorinated) C 2 _io-alkenyl, (optionally fluorinated) C 2 -io-alkynyl, or (optionally fluorinated) C 4 -o-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 - (NR 10 ) n - (GI) o -G2-G3, wherein
  • R 10 is H or C 1 -C 3 -alkyl
  • 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 4 -alkyl, C 2 -C 10 -alkyl, Alkenyl, or C2-C ⁇ o-Alkmyl, 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'Y 2 , or represents -CO-OY 3 ,
  • Y 1 and Y 2 are independently H, NH 2, - (CH 2 CH 2 0) 0 3- (CH 2) o- 3 Z '(for example, - (CH 2) 0 - 3 Z'), or - Z is CH (CH 2 W) 'represent, and Y 3 is H or - (CH 2) 0 - 3.
  • Z' group wherein Z 'is H, NH 2, S0 3 H, COOH, -NH-CO-CH 2 -CH 2 represents -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 , G_6 alkyl or optionally substituted with -NH 2 substituted aryl or benzyl;
  • R 2 represents H, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • Z is -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 ) 0 - 3 Z ', and Y 3 is H or -
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 , Ci-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 G_6 is alkyl;
  • R 4 represents H
  • A represents CO, SO, S0 2 , S0 2 NH or CNNH 2 ;
  • R 3 represents -L-1-L or -L-BINDER, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably a G-io-alkyl, C6 -io-aryl or coco-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-0-C6 io-aryl or C5-10-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 -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,
  • Groups 1-3 -NH-alkyl groups, 1-3 -N (alkyl) 2 groups, 1-3 NH ((CH 2 CH 2 0). 1 2 OH) groups, 1-3 NH 2 groups, or 1-3 - (CH 2 ) 0 - 3 Z groups, wherein Z is -H, halogen, -OY 3 , -SY 3 , -NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 , Y 1 and Y 2 are independently H, NH 2, or - (CH 2) 0 - 3.
  • Z ' represents, and Y 3 H, - (CH 2) o- 3 -CH (NHCOCH 3) Z' - ( CH 2 ) o- 3 -CH (NH 2 ) Z ', or - (CH 2 ) 0 - 3 Z', where Z 'is H, SO 3 H, NH 2 or COOH may be substituted (where "alkyl "preferably C is O-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'Y 2, or -CO-OY represents 3,
  • Y 3 is H or - (CH 2) o- 3 Z' 3 Z - wherein Y 1 and Y 2 are independently H, NH 2, or - (CH 2) 0 group, wherein Z 'is H, SO 3 H, NH 2 or COOH;
  • R 6 and R 7 are independently H or halogen (especially F, Cl, Br);
  • R 8 represents (optionally fluorinated) C 1-10 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, and their salts, solvates and salts of solvates.
  • R 1 , R 2 , R 3 , R 4 and R 5 have the abovementioned meanings (as indicated, for example, for formula (I) or (II)):
  • 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 n -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 BHC 15 1 040-A - 50 -, which in turn can be distinguished between chemically in vivo cleavable and enzymatically in vivo cleavable groups.
  • “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) to cleave 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):
  • 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 ).
  • BHC 15 1 040-A - 51 -
  • 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:
  • each LI is bound to the low molecular weight KSP inhibitor, for example a compound of formula (I), (Ia), (II), (IIa), (IIb), (IIca), (Ild), (He), ( Iii), (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
  • # 'de 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 C 1 -C 3 alkyl; BHC 15 1 040-A 54
  • G represents -NHCO-, -CONH- or ⁇ /; (R i U is preferably not NH 2 , though
  • 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 1 alkyl, C 2 -C 1 g alkenyl, or C2-C1 represents g-alkynyl, 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-, -SO 2 NHNH-, -CONHNH- and a 5 to 1 O-membered, aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from N, O and S, or -SO- may be interrupted (preferably
  • OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted.
  • G 2 is preferably 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 are mono- or polysubstituted by one or more of the groups BHC 15 1 040-A - 55 -
  • hydrocarbon chain including the side chains if present, with -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted.
  • Rx is H, Ci-C3-alkyl or phenyl.
  • # 1 is the binding to the KSP inhibitor and ffi is the binding to the coupling group to the antibody (e.g., 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-l, 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 can furthermore contain cyclic alkylene groups (cycloalkanediyl), for example 1,4-cyclohexanediyl or 1,3-cyclopentanediyl. These cyclic groups can BHC 15 1040-A - 56 - unsaturated.
  • aromatic groups may be present in the hydrocarbon group, for example phenylene.
  • one or more H atoms may optionally be substituted by C 1-10 -alkyl groups. 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 mono- or polysubstituted, identically or differently, by -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid.
  • the hydrocarbon chain can be mono- or polysubstituted, identically or differently, by one or more of the groups -O-, -S-, -SO-, S0 2 , -NH-, -CO-, -NHCO-, -CONH-, -NMe- , -NHNH-, -SO 2 NHNH-, -CONHNH- and a 5 to 1 O-membered, aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from N, O and S, -SO- or -SO 2 - be interrupted.
  • the linker corresponds to the following formula:
  • m is 0 or 1; BHC 15 1 040-A - 58 -
  • ⁇ represents the binding to the drug molecule
  • ⁇ represents the binding to the binder peptide or protein
  • LI has the formula -NR! Eat-up, where
  • R n 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
  • R 1 1 represents H or NH 2 ;
  • B represents - [(CH 2 ) x - (X 4 ) y ] w - (CH 2 ) z -,
  • X 4 is -O-, -CONH-, -NHCO- or represents.
  • linkers are particularly preferred in conjugates of the formula (I) or (II) in which the linker attaches to R4 by substitution of an H atom on Rl or in conjunction with a cleavable linker SGI, i. R1-L- # 1 represents or R4 -SG1-L- # 1, where # 1 represents the binding to the antibody.
  • the bonds to a cysteine residue of the antibody are preferably more than 80%, particularly preferably more than 90% (in each case based on the total number of linker bonds to the antibody), particularly preferably in one of the two structures of the formula A5 or A6 before:
  • # 'de 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 of 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 of up to 4 Heteroatoms selected from N, O and S, -SO- or -S02- may be interrupted, wherein the side chains, if present, with -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone , Sulfoxide or sulf
  • 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, X 2 C, and X 3 is N, and L 1 has the abovementioned meaning, L 2 and L 3 have the same meaning as LI, AK 1 for an (aglycosylated) anti-B 7 H 3 - Antibody bound via a cysteine residue and n is a number from 1 to 10.
  • AK1 is a human, humanized or chimeric monoclonal antibody or antigen-binding fragment thereof.
  • AK1 is an anti-B7H3 antibody which specifically binds the human Ig4 and / or the human and / or murine Ig2 isoform of B7H3, in particular one of the anti-B7H3 antibodies TPP-6497, TTP-6499, TPP -6501, TPP-6502, TPP-6515 ..
  • the anti-B7H3 antibody or the antigen-binding fragment is aglycosylated.
  • 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
  • x 0 or 1
  • 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
  • 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. Preferred as AK2 is a human, humanized or chimeric monoclonal, anti-B7H3 antibody or antigen-binding fragment thereof.
  • anti-B7H3 antibodies which specifically bind the human Ig4 and / or the human and / or murine Ig2 isoform of B7H3, in particular the anti-B7H3 antibodies TPP-6497, TTP-6499, TPP-6501, TPP-6502, TPP-6515.
  • the anti-B 7H3 antibody or the antigen-binding fragment is aglycosylated.
  • 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-CNH 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, L4 has the same meaning as LI, AK1 is an anti-B7H3 antibody linked via a cysteine residue is, and n is a number from 1 to 10.
  • the antibody is preferably an aglycosylated human, humanized or chimeric anti-B 7H3 monoclonal antibody or antigen-binding fragment thereof.
  • an anti-B 7H3 antibody which specifically binds the human 4Ig isoform, in particular one of the anti-B7H3 antibodies TPP-6497, TTP-6499, TPP-6501, TPP-6502 and TPP-6515In another preferred Embodiment, the anti-B7H3 antibody or the antigen-binding fragment is aglycosylated.
  • 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 coupling to a cysteine residue it is preferred to use one of the following compounds with the cysteine-containing binder, e.g. an antibody that may have been partially reduced, implemented:
  • R represents -H or -COOH
  • K is linear or branched, optionally substituted with G-C ⁇ alkoxy or -OH substituted G-Ce 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: BHC 15 1 040-A - 135 -
  • 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.
  • X 1 represents CH, X 2 C, and X 3 represents N)
  • SG 1 and L 1 have the same meaning as described above
  • L 2, L 3, and L 4 have the same meaning as L I
  • R and K have the same meaning as described above.
  • AK1 is a cysteine residue-linked anti-B7H3 antibody or antigen-binding fragment thereof
  • AK2 is a lysine-linked anti-B7H3 antibody or an antigen-binding fragment thereof.
  • AK1 and AK2 is an anti-B7H3 antibody that specifically binds the human 41g isoform, particularly one of the anti-B7H3 antibodies TPP-6497, TTP-6499, TPP-6501, TPP-6502, and TPP-6515.
  • the antibodies or antigen-binding fragments are present in an aglycosylated manner.
  • the anti-B7H3 antibody is preferably a human, humanized or chimeric monoclonal antibody or antigen-binding fragment thereof. Particularly preferred are anti-B7H3 antibodies or antigen-binding fragments which specifically bind the human Ig4 and / or the human and / or murine Ig2 isoform of B7H3, in particular the anti-B7H3 antibody TPP-6497, TTP-6499 , TPP-6501, TPP-6502, TPP-6515
  • the antibodies or antigen-binding fragments are aglycosylated. In this case, aglycosyl or aglycosylated antibodies have no glycans at the conserved N binding site in the CH2 domain of the Fc region.
  • 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 which can be used for linking are sulfur (in a BHC 15 1 040-A - 144 -
  • 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 group 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 a molecule having 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, e.g. Rabbit, llama, camel, mouse, or rat. In one embodiment, the antibody is of human or murine origin.
  • An antibody can e.g. be humane, 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.
  • intact antibody refers to antibodies comprising both an antigen-binding domain and the light and heavy chain constant domain BHC 15 1 040-A - 145 -
  • Domain may be a naturally occurring domain, or a variant thereof where multiple amino acid positions have been altered.
  • 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 Aug; 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 human antibody can e.g. 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.
  • complementarity determining region refers to those amino acids of a variable antibody domain necessary for binding to the antigen.
  • 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 BHC 15 1 040-A - 146 -
  • 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)).
  • CDR1 amino acid position 26-32
  • CDR2 50-52
  • CDR3 91-96
  • CDR3 variable light chain
  • CDR2 53-55
  • CDR3 96-101
  • 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), e.g. 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 antigen binding domain typically comprises one or more hypervariable regions of a ⁇ , eg the CDR, CDR2 and / or CDR3 region
  • 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 11 of the variable heavy chain, particularly preferred are the complete variable light and heavy chains, so amino acid 1 - 109 of the VL and 1 to 1 13 of the VH (numbering according to WO97 / 08320).
  • “Functional fragments” or “antigen-binding of the invention include, but are not limited to, Fab, Fab ', F (ab') 2 and Fv fragments, diabodies, single domain antibodies (DAbs), linearae ⁇ , single chains ⁇ (single-chain Fv, abbreviated scFv); and multispecific, such as bi- and tri-specific, ⁇ , formed from 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). Other ⁇ as “multi-specific” or “multi-functional” are those with identical binding sites.
  • Multispecific ⁇ can BHC 151040-A - 147 - be specific for different epitopes of an antigen or be specific for epitopes of more than one antigen (see eg WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt , et al., 1991, J. Immunol., 147: 60 69; U.S. Pat. Nos. 4,474,893; 4,7 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 '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 (e.g., a peptide linkage). Furthermore, 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 may be obtained from recombinant antibody libraries consisting, for example, of the amino acid sequences of a variety of antibodies generated from a large number of healthy volunteers. Antibodies can also be made 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. BHC 15 1 040-A - 148 -
  • 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 which 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)
  • ei Antibodies are usually produced by one or more purification steps.
  • 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 a Kd value thus preferably those with smaller Kd values as IQ"'7 M).
  • the antibody 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) that is not the predetermined antigen / target molecule or a closely related antigen / target molecule
  • the antibodies preferably have an affinity of at least 10.sup.- 7 M (as Kd value, thus preferably those having smaller Kd values than 10.sup.- 7 M), preferably of at least 10.sup.- 8 M, more preferably in the range of 10 " ⁇ M to 10 " ⁇ M.
  • 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 affinity preferably is not significantly affected (in general, the affinity is less than an order of magnitude reduced, eg a maximum of 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 better by at least a factor 2, preferably factor 5 or especially preferred factor 10 than at an independent other antigen, eg human serum albumin (the affinity can be determined eg by surface plasmon resonance spectroscopy) , BHC 15 1 040-A - 149 -
  • 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 cross-reactive with the target protein of at least one other species selected from the group of species consisting of mouse, rat and long-tailed macaque (Macaca fascicularis).
  • the target protein of at least one other species selected 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.
  • 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. Other methods of producing antibodies or antigenic BHC 15 1040-A-150 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 glycosylated or aglycosylated, i. in the latter case, they have no glycans at the conserved N-binding site in the CH2 domain of the Fc region.
  • an anti-B7H3 antibody or an antigen-binding fragment thereof is used, preferably TPP6497, 6499, 6501, 6502, 6515 or derived therefrom BHC 15 1 040-A - 151 -
  • the invention relates to conjugates with antibodies, antigen-binding antibody fragments thereof or variants thereof which have the following properties: binding to human B7H3, i. no binding to human B7H2 or human B7H4; Effectively and specifically killing B7H3-expressing tumor cells in vitro and in vivo.
  • the antibodies of the invention bind to epitopes which are particularly suitable for internalization after binding.
  • the antibodies of the invention are characterized by a low immunogenicity in human use, by as far as possible approaching the amino acid sequence of the antibodies to human germ line sequences.
  • a fully human antibody phage library (Biolnvent n-CoDeR Fab lambda library) was used to screen B7H3-specific human monoclonal antibodies of the present invention by protein panning (Hoogenboom HR, Nat Biotechnol 2005; 23 (3): 1105-16) with murine B7H3 as an immobilized target protein.
  • the antigens were desalted, following the instructions of the supplier, with about a two-fold molar excess of biotin-LC-NHS (Pierce, Cat No 21347) and Zeba desalination columns (Pierce, Cat No. 89889). Washed magnetic beads (Dynabeads) overnight with 800nM biotinylated protein at 4 degrees Celsius and then blocked for 1 hour at 4 degrees Celsius with blocking buffer (PBS with 3% Meadow Powder, 0.05% Tween-20).
  • the blocked Fab phage library was added to blocked TPP2202-loaded beads (Dynabeads streptavidin M280 - Invitrogen 112-06D) and incubated for 5 minutes at room temperature. This depletion step was repeated four times. The depleted Fab phage library was added to blocked beads loaded with TPP3762 and incubated for 60 minutes at room temperature.
  • TPP-3762 became -specific binders resuspended in PBS and used for amplification directly with for infection of the Escherichia coli strain TG1.
  • TPP-3762 Concentration of TPP-3762 reduced to 400nM to increase the selection pressure for high-affinity binders.
  • a second and third round of selection were performed on human B7H3-expressing cell lines.
  • the human renal carcinoma cell line A498 (ATCC, HTB-44) and the human adenocarcinoma cell line MCF-7 (ATCC, HTB-22) was used with lxlO 7 cells in the second and third round as selection antigen.
  • the cells were supplemented in 80% (v / v) RPMI 1640 GlutaMAX-I medium (Life Technologies, Cat. No. 61870-010) supplemented with 20% (v / v) fetal bovine serum (FBS, Life Technologies, Cat.
  • the cells were resuspended in 15 ml prewarmed PBS and incubated for 15 minutes at 37 degrees Celsius to allow internalization.
  • the cell membrane-bound Fab phage were removed by incubation with 1 ml of 76 mM citric acid.
  • the cells were washed again and centrifuged as above.
  • the internalized Fab phages were recovered by incubating the cell pellet with 1 ml lysis buffer (100 mM triethylamine) for 10 minutes and neutralizing in 0.5 ml IM Tris-HCl, pH 7.5.
  • the lysate fractions were amplified by infection of TG1 cells.
  • the resulting phage were sequenced and corresponding DNA sequences were cloned into a mammalian IgG expression vector and 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.
  • the antibodies were purified by protein A chromatography and characterized its binding to human B7H3 and human B7H2 and B7H4 by Elisa as described in AK Example 1.
  • TPP 6497, TPP6499, TPP6501, TPP6502 and TPP6515 showed attractive binding properties.
  • TPP-6497 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 9 and a light chain region corresponding to SEQ ID NO: 10.
  • TPP-6499 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 19 and a light chain region corresponding to SEQ ID NO: 20.
  • TPP-6501 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 29 and a light chain region corresponding to SEQ ID NO: 30.
  • TPP-6502 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 39 and a light chain region corresponding to SEQ ID NO: 40.
  • TPP-6515 is an antibody comprising a heavy chain region corresponding to SEQ ID NO: 49 and a light chain region corresponding to SEQ ID NO: 50.
  • TPP-6497 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 1 and a light chain variable region corresponding to SEQ ID NO: 5.
  • TPP-6499 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 11 and a light chain variable region corresponding to SEQ ID NO: 15.
  • TPP-6501 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 21 and a light chain variable region corresponding to SEQ ID NO: 25.
  • TPP-6502 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 31 and a light chain variable region corresponding to SEQ ID NO: 35.
  • TPP-6515 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 41 and a light chain variable region corresponding to SEQ ID NO: 45.
  • TPP-7611 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 1 and a light chain variable region corresponding to SEQ ID NO: 5.
  • TPP-8382 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 55 and a light chain variable region corresponding to SEQ ID NO: 57.
  • TPP-8564 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 55 and a light chain variable region corresponding to SEQ ID NO: 57.
  • TPP-8567 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 55 and a light chain variable region corresponding to SEQ ID NO: 57.
  • TPP-8322 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 63 and a light chain variable region corresponding to SEQ ID NO: 35.
  • TPP-8565 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 63 and a light chain variable region corresponding to SEQ ID NO: 35.
  • TPP-8568 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 63 and a light chain variable region corresponding to SEQ ID NO: 35.
  • TPP-8748 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 63 and a light chain variable region corresponding to SEQ ID NO: 68.
  • TPP-8750 is an antibody comprising a heavy chain variable region corresponding to SEQ ID NO: 63 and a light chain variable region corresponding to SEQ ID NO: 68.
  • Preferred embodiments of the anti-B7H3 antibody for coupling with linkers and / or toxophores according to the invention are the following antibodies:
  • SEQ ID NO: 52 represents the amino acid sequence of the extracellular domain of the human B7H3 polypeptide.
  • An antibody which binds to B7H3 or an antigen-binding fragment thereof comprising: a variable heavy chain comprising the variable heavy chain CDR1 sequence as represented by SEQ ID NO: 2, the heavy chain CDR2 variable sequence, such as represented by SEQ ID NO: 3 and the heavy chain variable CDR3 sequence as represented by SEQ ID NO: 4 and a variable light chain comprising the variable CDR1 light chain sequence represented by SEQ ID NO: 6, the variable CDR2 A light chain sequence represented by SEQ ID NO: 7 and a light chain variable CDR3 sequence represented by SEQ ID NO: 8, or a variable heavy chain comprising the variable CDR1 heavy chain sequence represented by SEQ ID NO Figure 12, the heavy chain CDR2 variable sequence as represented by SEQ ID NO: 13 and the heavy chain CDR3 variable sequence as represented by SEQ ID NO: 14 and a variable light chain send the variable CDR1 light chain variable sequence represented by SEQ ID NO: 16, the light chain variable CDR2 sequence represented by SEQ ID NO: 17, and the light chain variable CDR3 sequence represented by S
  • the antibody according to embodiment 4 or an antigen-binding fragment thereof comprising: a heavy chain variable sequence as represented by SEQ ID NO: 1 and a light chain variable sequence as represented by SEQ ID NO: 5 or a heavy chain variable sequence as represented by SEQ ID NO: 11 and a light chain variable sequence as represented by SEQ ID NO: 15 or a heavy chain variable sequence as represented by SEQ ID NO: 21, as well as a light chain variable sequence as represented by SEQ ID NO: 25 or a heavy chain variable sequence as represented by SEQ ID NO: 31 and a light chain variable sequence as represented by SEQ ID NO: 35, or a heavy chain variable sequence as represented by SEQ ID NO: 41, and a light chain variable sequence as represented by SEQ ID NO: 45, or a heavy chain variable sequence as represented by SEQ ID NO: 55, as well as a light chain variable sequence as represented by SEQ ID NO: 57.
  • the antibody according to any one of the preceding embodiments or an antigen-binding fragment thereof comprising: a heavy chain sequence as represented by SEQ ID NO: 9, and a light chain sequence as represented by SEQ ID NO: 10 or a sequence of the heavy chain A chain as represented by SEQ ID NO: 19, and a light chain sequence as represented by SEQ ID NO: 20 or a heavy chain sequence as represented by SEQ ID NO: 29, and a light chain sequence such as represented by SEQ ID NO: 30 or a heavy chain sequence as represented by SEQ ID NO: 39, and a light chain sequence as represented by SEQ ID NO: 40, or BHC 151040-A - 158 - a heavy chain sequence as represented by SEQ ID NO: 49, and a light chain sequence as represented by SEQ ID NO: 50, or a heavy chain sequence represented by SEQ ID NO: 59 and a light chain sequence as represented by SEQ ID NO: 60 or a heavy chain sequence as represented by SEQ ID NO: 61 and a light chain sequence as represented by SEQ ID NO:
  • the anti-B7H3 antibody is a humanized variant of one of the antibodies TPP-6497, TPP-6499, TPP-6501, TPP-6502, TPP-6515, TPP - 7611, TPP-8382, TPP-8564, TPP-8567, TPP-8322, TPP-8565, TPP-8568, TPP-8748 and TPP-8750.
  • the antibody according to any one of the preceding embodiments or an antigen-binding fragment thereof comprising: a heavy chain sequence as represented by SEQ ID NO: 9 containing at least one amino acid substitution selected from a group containing the substitutions R30S, S50A, V51I , A58T, L59Y, T97A, R98K and a light chain sequence as represented by SEQ ID NO: 10 containing at least one amino acid substitution selected from a group containing the substitutions P33T, G51S, S53N, N54Q, S77T, BHC 15 1 040-A - 159 -
  • a heavy chain sequence as represented by SEQ ID NO: 39 containing at least one amino acid substitution selected from a group containing the T31 S, G33A, H35S, T97A, R98K, L113T substitutions and a light chain sequence as represented by SEQ ID NO: 40 containing at least one amino acid substitution selected from a group containing the substitutions G25S, P33Y, P33T, N35Y, G51R, S53N, K54Q, Q90A, S91A, Y92W, S94D, W99V, G103E, K106E, or a sequence heavy chain as represented by SEQ ID NO: 49, which contains at least one amino acid substitution selected from a group containing the substitutions G33A, H35S, V40A, T57S, L104Y, L104W, Y107S, as well as BHC 15 1040-A - 160 - a light chain sequence as represented by SEQ ID NO: 50 containing at least one amino acid substitution selected from a group containing the substitution
  • the antibody according to one of the preceding embodiments comprising: The antigen-binding fragment according to one of the preceding embodiments or an antigen-binding fragment of an antibody according to one of the preceding embodiments which contains an scFv, Fab, Fab 'fragment or an F (ab) 2 fragment is.
  • 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 anti-B7H3 antibodies TPP-6497, TPP-6499, TPP-6501, TPP-6502 and TPP-6515.
  • the subject of the present invention accordingly also comprises humanized variants of the anti-B7H3 antibodies according to the invention, with the amino acid substitutions listed below, where P33T represents a substitution of P by T at amino acid position 33 of the respective chain of the antibody, G51S a substitution of G by S at position 51 of the respective chain of the respective antibody, etc.
  • TPP-6499 light chain G25S, Y26S, V29I, G31S, N33Y, N33T, N35Y, G51R,
  • 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, O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C, 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 distribution of active ingredient 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.
  • BHC 15 1 040-A - 162 - 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, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylpiperidine, N-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 salts) and ammonium salt
  • 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).
  • KSP-L- is a compound of the following formula (I), (Ia), (II), (IIa), (IIb), (IIc), (IId), (Ile) (III), (IIj), (Ilk) or the following formula (Iii)
  • the binder is an anti-B7H3 antibody, which may be aglycosylated, or an antigen-binding fragment thereof.
  • Anti-B7H3 antibodies which specifically bind the human Ig4 and / or the human and / or murine Ig2 isoform of B7H3, in particular the anti-B7H3 antibodies TPP-6497, TTP-6499, TPP-6501, are particularly preferred , TPP-6502, TPP-6515 .., where n is a number from 1 to 10:
  • A is CO (carbonyl);
  • R 1 -L- # 1 H, -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 (to form a pyrrolidine ring) are -CEh-CHR 11 - or -CHR n -CH 2 -, wherein R 11 is H; BHC 15 1 040-A - 164 -
  • R 5 is H or F
  • R 6 and R 7 are independently H, (optionally fluorinated) G-3-alkyl, (optionally fluorinated) C 2 _4 alkenyl, (optionally fluorinated) C 2 -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
  • R 10 is H, NH 2 or C 1 -C 3 alkyl; Gl -NHCO- or represents;
  • n 0 or 1
  • 0 is 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
  • - 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 KSP inhibitor and ffi is the binding to the coupling group to the antibody (e.g., L2).
  • KSP-L- is a compound of the following formula (I), (Ia), (II), (IIa), (IIb), (IIc), (Ild), (Ile) , (Ilf), (Iii), (Ilj), (Ilk) or the following formula (Il'g) or the following formula (Ilg), the binder is in a preferred embodiment aglycosylated anti-B7H3 antibody, and n is a number from 1 to 10:
  • R 1 -L- # 1 H, -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 (to form a pyrrolidine ring) represent -CH 2 -CHR n - or -CHR n -CH 2 -, wherein R 11 represents H;
  • R 3 -L- # l or a Ci-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) n -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 are independently H, (optionally fluorinated) G-3-alkyl, (optionally fluorinated) C 2 _4 alkenyl, (optionally fluorinated) C 2 -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
  • # 'de 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 ⁇ /;
  • BHC 15 1 040-A - 168 - n is 0 or 1;
  • 0 is 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
  • aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from N, O and S, or -SO- may be interrupted (preferably where the side chains, if present, may be substituted with -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNEh, sulfonamide, sulfone, sulfoxide, or sulfonic acid,
  • # 1 is the binding to the KSP inhibitor and ffi is the binding to the coupling group to the antibody (e.g., L2),
  • KSP-L- is a compound of the following formula (II), (IIa), (IIb), (IIc), (Ild), (Ile), (IIIf), (IIg), (III), (IIj), (Ilk) or the following formula (IIh)
  • the binder is a aglycosylated anti-B7H3 antibody in a preferred embodiment, 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 (to form a pyrrolidine ring) represent -CH 2 -CHR n - or -CHR n -CH 2 -, wherein R 11 represents H;

Abstract

La présente invention concerne de nouveaux conjugués liant-principe actif (ADC), des métabolites efficaces de ces ADC, des procédés de préparation de ces ADC, l'utilisation de ces ADC pour le traitement et/ou la prévention de maladies ainsi que l'utilisation de ces ADC pour la production de médicaments servant au traitement et/ou à la prévention de maladies, notamment de maladies hyperprolifératives et/ou angiogéniques, telles que les maladies cancéreuses. De tels traitements peuvent être effectués en tant que monothérapie ou en combinaison avec d'autres médicaments ou d'autres mesures thérapeutiques.
EP16733024.0A 2015-06-23 2016-06-20 Conjugués anticorps-principe actif (adc) d'inhibiteurs de ksp avec des anticorps anti-b7h3 Pending EP3313522A1 (fr)

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CA2990411A1 (fr) 2016-12-29
WO2016207104A1 (fr) 2016-12-29
TW201718020A (zh) 2017-06-01
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US20200138970A1 (en) 2020-05-07

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