EP3313525A1 - 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
EP3313525A1
EP3313525A1 EP16736012.2A EP16736012A EP3313525A1 EP 3313525 A1 EP3313525 A1 EP 3313525A1 EP 16736012 A EP16736012 A EP 16736012A EP 3313525 A1 EP3313525 A1 EP 3313525A1
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EP
European Patent Office
Prior art keywords
alkyl
cooh
antibody
seq
represented
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.)
Withdrawn
Application number
EP16736012.2A
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German (de)
English (en)
Inventor
Hans-Georg Lerchen
Anne-Sophie Rebstock
Yolanda Cancho Grande
Sven WITTROCK
Uwe Gritzan
Pedro Paz
Melanie Fischer
Juergen Franz
Julian Marius GLÜCK
Stephan MÄRSCH
Beatrix Stelte-Ludwig
Christoph Mahlert
Ernst Weber
Simone Greven
Sandra Berndt
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Bayer Pharma AG
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Bayer Pharma AG
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Publication date
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Publication of EP3313525A1 publication Critical patent/EP3313525A1/fr
Withdrawn legal-status Critical Current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
    • A61K47/6849—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6863—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C07K2317/41—Glycosylation, sialylation, or fucosylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • ADCs Antibody-drug conjugate
  • 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 hyperpropriiferative and / or angiogenic diseases such as, for example, cancers.
  • ADCs binder-drug conjugates
  • Such treatments may take place as monotherapy or in combination with other medicaments or other therapeutic measures.
  • Cancers are the result of uncontrolled cell growth in a variety of tissues, in many cases the new cells invade existing tissues (invasive growth) or they metastasize to distant organs. Cancers occur in various organs and often have tissue-specific disease courses. Therefore, the term cancer as a generic term describes a large group of defined diseases of various organs, tissues and cell types.
  • early stage tumors may be removed by surgical and radiotherapeutic measures.
  • metastatic tumors can only be treated palliatively by chemotherapeutic agents.
  • the goal here is to achieve the optimal combination of improving the quality of life and extending the lifetime.
  • ADCs antibody drug conjugates
  • cytotoxic agent itself or another cytotoxic metabolite formed therefrom is released within the tumor cell, where it can exert its direct and selective action
  • damage to normal tissue could be kept within significantly narrower limits compared to conventional cancer chemotherapy [See, eg, JM Lambert, Curr. Opin. Pharmacol., 5, 543-549 (2005); AM Wu and PD Senier, Nat. Biotedmol.
  • WO2012 / 171020 describes ADCs in which several toxophore molecules are linked to an antibody via a polymeric linker.
  • the possible toxophors mentioned in WO2012 / 171020 include the substances SB 743921, SB 715992 (Ispinesib), MK-0371, AZD8477, AZ3146 and ARRY-520.
  • Kinesin spindle protein inhibitors Kinesin spindle protein (KSP, also known as Eg5, HsEg5, KNSL1, or KIF11) is a kinesin-like motor protein that is essential for the function of the bipolar mitotic spindle. Inhibition of KSP leads to mitotic arrest and apoptosis over a prolonged period (Tao et al., Cancer Cell 2005 Jul 8 (1), 39-59).
  • KSP inhibitors After finding the first single-pass 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 / 05922, 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 ⁇ - ⁇ - ⁇ - ⁇ - ⁇ - ⁇ -3 ⁇ - ⁇ 7 ⁇ 3- ⁇ 1 ⁇ 6 ⁇ 8 with compounds of the following formula (I), wherein one or more of the compounds of formula (1) with the antibody via a linker L is connected or are.
  • aglycosylated antibodies have no glycans at the consequent 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 a human, humanized or chimeric monoclonal antibody
  • an anti-B 7H3 antibody that specifically binds the human Ig4 and / or the human and / or murine Ig2 isoform of B7H3, especially the anti-B7H3 Antibody TPP-5706 and its humanized variants.
  • R 1 represents H, -L- # 1, -MOD or - (CH 2 ) o-3Z, wherein 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, H 2, - (CH 2 CH 2 0) o-3- (CH2) o-3Z '(for example, - (CH 2) 0 -3Z'), or -CH (CH 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-CHYVsCOOH, wherein represents WH or OH,
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 substituted, Cs-6 alkyl or optionally -NH 2 substituted Aryi or benzyl;
  • R 2 is H, -MOD, -CO-CHY 4 -NHY 5 or - (CH 2 ) o. 3 Z represents,
  • 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-3Z ', and Y J is H or -
  • Y * is linear or branched, optionally with -NHCONH? substituted, Ci- ⁇ alkyl or optionally substituted with -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY * -NH 2 , wherein Y * represents linear or branched CW alkyl;
  • SGi ys represents a cleavable by a lysosomal enzyme group, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a C i - io-alkyl, Cs-10 aryl or Ce- ⁇ o- aralkyl, Cs -io-heteroalkyl, ci-io-alkyl-O-Ce-io-aryl, Cs-io-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkoxy, Ci-io-alkoxy, Ce -io-aryloxy or Ce-io-aralkoxy, C5-10 Heteroaraikoxy-, Ci-io-alkyl-O-Ce-io-aryloxy, C5-1 o-heterocycloalkoxy group which is mono- or polysubstituted with - NH 2 , -NH-alky
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 V 3 Z ', and Y 3 is H or - CC ' l I -)... / .. where Z 1 is H, SO 3 H, NH 2 or COOH darstelit;
  • Y 4 is linear or branched, optionally substituted with -NHCONH2, Ci-s alkyl or optionally substituted with -NH 2 substituted aryl or benzyi and Y 5 is H or ⁇ CO-CHY 6 -NH 2 , wherein Y 6 linear or branched Ci -e is alkyl;
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR 11 - or -CHR "-CH 2 -, wherein R 1 'is H, NH 2 , SO 3 H, COOH, SH, halogen (especially F or Cl C represents i-), C M Alkyi, Ci- * HaIoalkyl, Ci-4 alkoxy, hydroxyl-substituted C1-4 alkyl, COO (4 alkyl), or OH;
  • A represents CO, SO, SO 2 , SO 2 NH or CNNH 2 ;
  • R ' is L, MOD, or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, Grappe, preferably -L- # l or a C M 0 -alkyl-, Ce -io-aryl or Ce-io-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-0-C6-io-aryl or C5- 10 heterocycloalkyl group, with 1-3 -OH Groups, 1-3 halogen atoms, 1-3 halogenated alkyl groups (each having 1 -3 halogen atoms), 1 -3 O-alkyl groups, 1-3 -SH groups, 1-3 -S-alkyl groups, 1 -3 - O-CO-alkyl groups, 1-3 -Q-CO-NH-alkyl groups, 1-3 -NH-CO-alkyl groups, 1 -3 -NH-
  • alkyl is preferably Cj-io-alkyl
  • R 5 is H, MI ,, NO 2 , halo (especially F, Cl, Br), -CN, CF 3 , -OCF 3 , -CH 2 F, -CH 2 F, SH or - (CH 2) -jZ, where Z is Represents -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 - (Ci i), ./., where Z' is H, SO 3 H, NH 2 or COOH; represents,
  • R 6 and R ' are each independently H, cyano, (optionally fluorinated) Ci-io-alkyl, (optionally fluorinated) C 2 -io-alkenyl, (optionally fluorinated) C 2 -io ⁇ Aikmyi, hydroxy, N0 2 , NH 2 , COOH or halogen (especially F, Cl, Br),
  • R 8 is (optionally fluorinated) Ci-io-Alkyi, (optionally fluorinated) C 2-10 alkenyl, (optionally fluorinated) C2-10- alkynyl, (optionally fluorinated) C 4-10 Cycloalk.yi OR (CH 2 ) o... 2 - (HZ) where HZ is a 4 to 7-membered heterocycle having up to two heteroatoms selected from N, O and S, each of which is represented by -OH, CO2H or NH? may be substituted;
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ;
  • R ', R ⁇ 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 - (N 10 ) n - (GI) o -G2-G3, wherein R ] 0 represents H or C iC 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, C1 -C1 g-alkyl, C2-C1 Q Alkenyl, or C 2 -C ⁇ Q-alkynyl, each with
  • H-CN H 2 sulfonamide, Sulfone, sulfoxide, or sulfonic acid
  • G3 is -H or -COOH
  • the group - MOD preferably has at least one -COOH group; and their salts, solvates, salts of solvates and epimers.
  • the conjugates according to the invention may formerly have 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 precursor Konj ugats.
  • 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 can be accomplished by substitution of a hydrogen atom on R 1 , R 3 or R 4 in formula ( ⁇ ) by the linker.
  • any functional groups present may also be present in protected form. Prior to the conjugation step, these protecting groups are removed by known methods of peptide chemistry.
  • the conjugation can be carried out chemically in various ways, as exemplified in Schemes 20 to 31 in the Examples. It is particularly possible, the low molecular weight KSP inhibitor for If necessary, modify the conjugation to the linker, eg by introducing protective groups or leaving groups for easier substitution.
  • 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 is H, -L-BINDER, -MOE) or - (CH 2 V 3 Z, where Z is -H, - HY 3 , -
  • Y 1 and Y 2 independently of one another H, NH 2 , - ⁇ ' ⁇ ))., ⁇ ( ⁇ ⁇ ), .. 7 /, ⁇ ,
  • Y 3 represents H or - (CH 2 ) o-3Z 1 ,
  • W represents H or OH
  • R 2 represents H, -MOD, -C (-O) -CHY 4 -NHY 5 or - (CH 2 ) o-3Z,
  • R 2 and R 4 together (to form a pyrrolidine ring) -CH 2 -CHR ! L - or
  • CM alkyl CM haloalkyl, G 4 alkoxy, hydroxyl substituted CM alkyl, COO (C - 4 alkyl.), Or -OH darsteilt;
  • Z is -H, halogen, -OY 3 , -SY 3 , HY 3 , -CO-NY'Y 2 , or -CO-
  • OY 3 represents,
  • Y 'and Y 2 are independently H, NH 2 , or - (CH 2 ) o-3Z', and Y 3 is H or - (CH 2 V 3 Z ', where Z' is H, South, H 2, or COOH;
  • Y 4 is linear or branched, optionally substituted by -NHCONtb, Ci -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 Cw Alkyl;
  • SG j y g represents a cleavable by a lysosomal enzyme group, in particular a group consisting of a di- or tripeptide
  • R h is a Ci-10-alkyl, Cs-io-aryl or Ce-io- aralkyl, Cs -io-heteroalkyl, Ci-io-alkyl-O-Ce-io-aryl, Cs-io-heterocycloalkyl, heteroaryl, Heteoaryl-alkyl, heteroaryl-alkoxy, Ci-io-Alfcoxy-, Ce io-aryloxy or Ce ⁇ o-aralkoxy, C5-10 heteroaralkoxy, Ci-io-alkyl-O-Ce-io-aryloxy, Cs-io-Heteroeyeloalkoxy group, one or melärfach with - NH 2 , -NH-alkyl, -N
  • Y 1 and Y 1 are independently H, NH 2 , or - (CH 2 ) o-3 l , and ⁇ 'H or -
  • Y * is linear or branched, optionally substituted with -NHCONH 2 , C1-6 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 Cw represents alkyl;
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR ] i - or -CHR I] -CH 2 -, where R ! i H, NH2, SO3H, COOH, SH, halo (especially F or Cl), CM alkyl, Cw Haioalkyl, CwAlkoxy, hydroxyl-substituted CM alkyl, COO (Ci. 4 alkyl), or OH;
  • Y 2 independently represent H, NH 2 , or - (Ctb VsZ ', and Y 3 H, - (CH 2 ) o-3-CH (NHCOCH 3 ) Z', - (CH 2 ) o-3-CH (NH 2 ) Z ', or represents - (CH 2 ) 0 -3Z', where Z 'represents H, SO 3 H, NH 2 or COOH,
  • alkyl is preferably ⁇ -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 ) o-3Z, wherein Z is -H, -OY 3 , -SY 3 , halogen, NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 , wherein Y 1 and Y 2 are independently H, NH 2 , or - (CH 2 V 3 Z 'and Y is J or - (CH 2 J 0 -3Z', where Z 'is H, SO 3 H, or COOH.
  • R 5 (optionally, fluorinated) C 10 -alkyl, (optionally fluorinated) C 10 -alkenyl, (optionally fluorinated) C 2-10 -alkynyl, (optionally fluorinated) 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 which groups is substituted with -OH , CO2H or NH 2 may be substituted;
  • R 9 is H, F, CH 3 , CF 3 , CH 3 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 multiple drug molecules, wherein a member of R ! R 3 , and R 4 represents -L-Binder;
  • R ° and R '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), wherein -MOD is - (NR 10 ) n - (GI) o -G 2 -G 3, wherein R 10 is H or C 1 -C 3 -alkyl;
  • Gl M represents ICO- or -CONH- (wherein when Gl represents -NHCO-, R 10 is not NH 2 );
  • n 0 or 1
  • o 0 or 3
  • G2 is a straight-chain and / or branched hydrocarbon group having 1 to 10 carbon atoms which is mono- or polysubstituted by one or more of the groups -O-, -S-, -
  • FIG. 1 Internalization behavior of the specific B7H3 antibody TPP5706 in the human renal cancer cell line A498.
  • the invention provides conjugates of an anti-B7H3 antibody such as TPP-5706 as well as aglycosylated and / or humanized variants of TPP-5706 with one or more drug molecules.
  • a kinesin spindle protein inhibitor KSP inhibitor linked to the antibody via a linker L.
  • the conjugate according to the invention can be represented by the general formula
  • BINDER for the anti-B7H3 antibody such as TPP-5706 and aglycosylated and / or humanized variants of TPP-5706, L for the linker, KSP for the CPSP inhibitor, and n for a number from 1 to 50 , preferably 1.2 to 20 and particularly preferably 2 to 8 stands.
  • 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 an aglycosylated human, humanized or chimeric anti-B7H3 monoclonal antibody or antigen binding fragments thereof.
  • an anti-B7H3 antibody which specifically binds the human 4Ig isoform, in particular the anti-B7H3 antibody TPP-5706 and its humanized variants such as TPP-6642 and TPP-6850.
  • 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 each shown as being preferred or particularly preferred, if appropriate in combination with the linkers respectively illustrated 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 valency of the designated atom is less than the present value Circumstances is not exceeded. 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 for 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 "3, 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 mono- or mono-monosubstituted.
  • the meanings of all radicals that occur easily 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 (C 1 -C 10 -alkyl), generally 1 to 6 (C 1 -C 4 -alkyl), preferably 1 to 4 (C 4 -C 4 -alkyl), and particularly preferably 1 to 3 carbon atoms (Ci-Ca-alkyl).
  • Heteroalkyl represents a straight-chain and / or branched hydrocarbon chain having 1 to 10
  • Sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted.
  • R * is -H, Ci-C ⁇ -Alky] - 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 (C -C -Cl) Alkenyl), it being understood that when the acyl group contains more than one double bond, the double bonds may be isolated from each other or conjugated with each other.
  • Aikinyl stands for "a straight-chain or branched monovalent hydrocarbon chain having a triple bond and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (C 1 -C 10 -alkynyl), in particular 2 or 3 carbon atoms (C 2 -C 4)
  • the C 2 -C 6 -alkynyl group is an ethynyl, prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-1-enyl 2-inyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2 -inyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-yny
  • 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 (Cs-Cn-cycloalkyl).
  • a monocyclic carbon stands for a monovalent one
  • Hydrocarbon radical having generally 3 to 10 (C 3 -C 10 -cycloalkyl), preferably 3 to 8
  • a monocyclic hydrocarbon radical mention may be made:
  • a cyciopropyl cyclobutyl, cyclopentyl, cyclohexyl and
  • a bicyclic hydrocarbon radical is a hydrocarbon radical having usually 3 to 12 carbon atoms (Cs-C ⁇ cycloalkyl), in which case a fusion of two to understand saturated ring systems that share two atoms directly adjacent to each other.
  • exemplary and preferred for a bicyclic hydrocarbon radical are: bicycio [2.2.0] hexyi, bicycio [3.3.0] octyl, bicyclo [4.4.0] decyl, bicyclo [5.4.0] undecyl, bicyclo [3.2. G] heptyl, bicyclo [4.2.0] octyl, bicyclo [5.2.0] nonyl, bicyclo [6.2.0] decyl,
  • Heterocycloalkyl represents 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 nonionic cyclic ring system according to the present invention may have 3 to 8, preferably 4 to 7, particularly 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:
  • Azepanyi 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
  • heterocycloalkyl 4 to 7-membered, saturated heterocyclyl radicals with bis to two heteroatoms from the series O, N and S 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 being 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 aphthyi and phenyl; preferred is phenyl or a phenyl radical.
  • Ce-io-Aralkyl- stands in the context of the invention for a monocyclisch.es aromatic aryl, exemplified by phenyl, to which a C rtVAlkyl distr is bound.
  • An exemplary ceto-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
  • the heteroaryl group may be a 5-membered heteroaryl group such as thienyl, furol, pyrrolyl, oxazolyl, thiazolyl, imidazoliy, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group such as, for example, pyiidinyl, pyridazinyl, pyrirnidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group such as carbazolyl, aeridinyl or phenazinyl; or a 9-membered heteroaryl group such as benzofuranyi, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazoiyl, benzothiazolyl, benzotri
  • 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.
  • 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:
  • Heteroalkoxy represents a straight-chain and / or branched hydrocarbon chain having 1 to 10 carbon atoms, which is bonded via -O- to the remainder of the molecule and which furthermore comprises one or more of the groups -O-, -S-, - R - V -,
  • Sulfone, sulfoxide, or sulfonic acid may be substituted
  • Sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted.
  • R * is -H, Ci-C3 ⁇ 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 aikyl, 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.
  • the low molecular weight KSP inhibitor for conjugation to the linker optionally, for example, 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.
  • Y ! and Y * independently of one another are H, NH 2 , - (CH 2 CH 2 O) o-3- (CH 2) o-3Z '(for example - Cft ⁇ wZ 1 ), or -CH (CH 2 W) Z', and Y 3 represents H or - (CH 2 V 3 Z ', wherein Z' is H, NH 2 , SO 3 H, COOH, -NH-CO-CH 2 -CH 2 -CH (NH 2 ) COOH or - (CO-NH-CHY 4 ) i, 3 COOH where represents WH or OH,
  • Y 4 is linear or branched, optionally substituted by ⁇ NHCONH2, Ci-e alkyl or optionally -NH2 substituted aryl or benzyl;
  • R 2 represents H, -MOD, -CO-CHY 4 -NHY 5 or - (CH 2 ) o- 3 Z,
  • Z is -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 ,
  • ⁇ 'and Y 2 are independently H, NH 2 , or - ( ' CH 2 ) o-3Z ', and Y 3 is H or -
  • R 4 is H, L # 1, -SG is lys - (CO) 0 " i -R 4 ', -CO-CHY 4 -NHY 5 or ⁇ ((!) ,, ./.,
  • SG ] YS represents a group cleavable by a lysosomal enzyme, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a Cwo-alkyl, Cs-io-aryl or Ce- ⁇ o- aralkyl, Cs-io Heteroalkyl, Ci-io-alkyl-O-Ce-io-aryl, Cs-io-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkoxy, Ci-alkoxy, Ce-io-aryloxy - or Ce-io-aralkoxy, Cs-io heteroaralkoxy, C ⁇ ⁇ o-alkyl-O-Ce-io-aryloxy, Cs io-Heterocycloalkoxy Grappe, the one or more times with - NH 2 , -NH Alkyl, -N (alkyl) 2
  • Z represents -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-Y'Y 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 3 Z ', and Y 3 H or -
  • Y 4 is linear or branched, optionally with-NHCONHz substituted, C i -6 alkyl or optionally substituted with - : H 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2, wherein Y 6 linear or branched Cw represents Alkyi;
  • R 2 and R 4 together (to form a pyrrolidine ring) -CH 2 -CHR 1! - or -CHR 1 1 -CH 2 -, where R ! 1 H, NH 2 , SO 3 H, COOH, SH, halogen (especially F or CI), CM Alkyi, C! 4 is haloalkyl, d. Alkoxy, hydroxyl-substituted C M Alkyi, COO (C w Aikyl) or OH;
  • A represents CO, SO, SO 2, SO 2 H or (NM!
  • R 3 represents -L- # 1, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably a Ci-io-alkyl, Cwo-aryl or C 10-Araikyl, Cs-i o-Heteroalkyl, Ci-io-alkyl-O-Ce-io-aryl or Cs-s o-heterocycloalkyl group having 1-3 -OH groups, 1-3 halogen atoms , 1-3 halogenated alkyl groups (each having 1-3 halogen atoms), 1-3 O-alkyl groups, 1-3-SH groups, 1-3-S-alkyl groups, 1-3
  • 0-CO-alkyl Grappen 1-3 -O-CO-NH-Alkyi groups, 1 -3 1 -3 -NH-CO-NH-alkyl groups, 1-3 -S (0) n -alkyl groups, 1-3 -SO 2 -H-alkyl groups, 1-3 -NH-alkyl groups, 1-3 - N (alkyl) 3 Grappen, 1-3 -NH ((CH 2 CH 2 0) ⁇ _ 2 oH) groups, -NH2 groups, or 1 -3
  • R s is H, -MOD, Nile ;. NC, halogen (in particular F, Cl, Br), -CN, CF 3 , -OCF 3 , (II I * (II) F. SH or - (CH 2 V 3 Z, where Z is -H, - OY 3 , -SY 3 , halogen, NHY 3 , -CO-Y'Y 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another denote H, H 2 , or - (CH 2 V 3 Z ', and Y 3 represents H or - (C 1; i,: /, where Z' is H, SO 3 H, N) or COOH;
  • R 6 and R 7 independently of one another are H, cyano, (optionally fluorinated) C 3 O -alkyl, (optionally fluorinated) C 2 -alkenyl, (optionally fluorinated) C 2 -alkenyl, hydroxy, N 2 , H 2 , COOH or halogen (especially F, Cl, Br),
  • R ° (optionally fluorinated) C 2 O -alkenyl, (optionally fluorinated) C 2 -alkenyl, (optionally fluorinated) C 2-10 -alkynyl, (optionally fluorinated) C 4 -io-cycloalkyl or - (CH 2 ) o- 2 »(HZ 2 ) where HZ 2 is a 4 to 7-membered heterocycle having up to two heteroatoms selected from N, O and S (preferably oxetane), each of which is -OH, CO2H or H 2 may be substituted; wherein one of the substituents R 1 , R 3 and RL represents -l,
  • R 9 is H, F, CH 3, CF 3, CH 2 F or CHF 2 ; where -MOD is - ( NR10 ) r ⁇ GI) o -G2-G3, where
  • R "II or Ci-C, alkyl represents:
  • G is -NHCO-, -CONH- or ⁇ / (where if G is -NHCO- or
  • n 0 or 1
  • o is 0 or 1; and 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 4 represents H or -SG [vs - (CO) Q... I -R 4 ', where SG lvs and R 4 ' have the same meaning have as above.
  • R ! 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 binds is a stereocenter which may be in the L and / or D configuration.
  • Y 1 and Y 2 independently of one another are H, NH 2 , - (CH z CH 2 O) o-3- (CH 2) o. 3 Z '(for example - (CH 2 V 3 Z'), or -CH (CH 2 W) Z ', and Y 3 represents H or - (CH 2 3 Z ', where Z' is H, NH 2 , SO 3 H, COOK, -NH-CO-CH 2 -CH 2 -CH (Mi 2 ) COOH or - (CO-H-) CHY , ) i -3 COOH, wherein represents WH or OH;
  • Y 4 is linear or branched, optionally substituted with-NHCONH2, Ci-e alkyl or optionally substituted with -NH 2 substituted aryl or benz l.
  • R 2 and R 4 are independently H
  • ys represents a group cleavable by a lysosomal enzyme, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a Ci-io-alkyl, Cs-io-aryl or Ce- ⁇ o- aralkyl, Cs -io-heteroalkyl, C 1-10 -alkyl-0-C6-io-aryl, Cs-io-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkoxy, Ci- -alkoxy-, ce- io-aryloxy or Ce-io-aralkoxy, C5.10-heteroaralkoxy, Ci-io-alkyl-O-Ce-io-aryloxy, Cs-io-heterocycloalkoxy group, each one or more times with - NH 2 , -NH-alkyl, -N (alkyl) 2
  • Y 'and Y 2 are independently H, NH 2 , or - (CH 2) o-3Z', and Y J is H or - i C i ⁇ . ), ⁇ ⁇ / ⁇ Where Z 'is H, SO3H, NH2 or COOH;
  • Y 4 is independently linear or branched, optionally substituted by -NHCONH 2 , C 1-6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl, wherein Y 4 linear or branched, optionally substituted with -NHCONtb, C 1-6 Alkyi or optionally substituted with -NH 2 substituted aryl or benzyl and Y 5 is H or -CO-CHY 6 -NH 2 , wherein Y 6 represents linear or branched Ci - ⁇ Alkyi;
  • A represents CO, SO, SO 2, SO 2 H or CNNH;
  • R 3 represents an optionally substituted alkyl, aryl, heteroaryl, heteroalkyl, helerocycloalkyl group, preferably -L- # 1 or a CWo-alkyl, C 1-10 -aryl or C 6 -o-aralkyl-, C 5- 10- heteroalkyl, C o -alkyl-O-Ce-io-aryl or Cs-i o-heterocycloalkyl group having with 1-3 -OH groups, 1 -3 halogen atoms, 1-3 halogenated Alkyi deficit (each 1-3 halogen atoms) ,, 1 -3 O-Alkyi 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-CQ-NH-alkyl
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - CH 2 ) o-3Z ', and Y J H, - (CH 2 V 3 -CH (NHCOCH 3 ) Z', - (CH 2 ) o-3-CH (NH 2 ) Z ', or - (CH 2 ) 0 -3Z', where Z 'is H, SO 3 H, NH 2 or COOH,
  • Alkyi is preferably C where- Alkyi
  • R 5 represents H, F, NH 2 , NO 2 , halogen, SH or -I (IN, etc. ) , wherein Z is -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY ! Y 2 or -CO-OY 3 ,
  • Y 'and Y 2 are independently H, NH 2 , or - (CFi 2 ) 0 -3Z', and Y 3 Fi or - i C ⁇ ⁇ . h .7 represents: where Z 'is H, SO 3 H, NH 2 or COOH;
  • R 6 and R ' are independently Fi, cyano, (optionally fluorinated) Ci -SO-alkyl, (optionally fluorinated) C2-10- alkenyl, (optionally fluorinated) C 2 represent .io- alkynyl, hydroxy or halogen, R 8 (optionally, fluorinated) Ci-io-alkyl, (optionally fluorinated) or optionally substituted oxeiane; and
  • R 9 is H, F, CH 3 , ( ' ! ' : HI or CHF 2 , and their salts, solvates, salts of solvaie and epimers.
  • R 3 or R 4 also represents -L- # 1, where L is the linker and # 1 is the bond to the antibody. That is, in the case of the conjugals, one of the substituents R 1 , R 3 or R 4 represents -L- # 1, wherein -L- # 1 represents the bond to the antibody. In a preferred embodiment of the formula (I) or (Ia), one of the substituents R 1 or R 3 represents -L- # I. In this embodiment it is particularly preferred if R 4 is H or -SG 1vs - (CO) Q_ ] -R 4 ', where SG LVS and R 4 ' have the same meaning as above.
  • the binder is preferably a human, humanized or chimeric monoclonal antibody or antigen-binding fragment thereof.
  • the antibody is preferably an aglycosylated human, humanized or chimeric anti-B7H3 monoclonal antibody.
  • Particularly preferred is an anti-B7H3 antibody which specifically binds the human 4Ig isoform, in particular the anti-B7H3 antibody TPP-5706 and its humanized variants such as TPP-6642 and TPP-6850.
  • 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 naturally present in the protein, introduced by biochemical methods or preferably can be generated by prior reduction of disulfides of the binder.
  • CO carbonyl
  • R ' is preferably -L- # l, H, -COOH, -CONHNH2, - (CH 2 ) i- 3 NH 2 , - € ONZ (( (CH 2 ) 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 decrease (to form a pyrrolidine ring) -CH 2 -CHR 1 1 - or -CHR i! ⁇ CH2 ⁇ dars money, wherein R "represents H.
  • R 4 is -L-# l also preferred, wherein -L- # l is a cleavable linker, preferably a cleavable linker intracellularly enzymatiseh.
  • R 3 is preferably -L- # l or a C i-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, (alkyl) 2 , or NH 2 may be substituted (wherein alkyl is preferably C1 ..3 alkyl means).
  • R 5 is preferably H or F.
  • R 6 and R ' are independently of each other preferably H, (optionally fluorinated) Cw-AikyL (optionally fluorinated) C 2 -4 alkenyl, (optionally fluorinated) C 2 -4 ⁇ alkynyl, hydroxy or halogen.
  • R 8 is preferably a branched C s .5- alkyl group, especially a group of formula - C (CH 3) 2 - (CH 2) o- 2 -R y wherein R y - ⁇ , OH, C0 2 H, or H 2 , or a (optionally fluorinated) C 5-7 -cycloalkyl Particularly preferred is a group of the formula or a cyclohexyl group.
  • R 9 is preferably H or F.
  • A is CO (carbonyl);
  • 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 ! 1 -CH 2 -, where R 1! H represents; or R 4 is -L- # 1 and R 2 is H; R '-L- # l or a phenyl group which may be substituted one or more times by halogen (in particular F) or optionally fluorinated C ⁇ .
  • Aikyl or represents an optionally fluorinated Ci-io-alkyl group, optionally with -OY 4 , -SY 4 -O-CO-Y 4 -O-CO-NH-Y 4 , NH-CO-Y 4 , -NH-CO-HY 4 , S (O) "- Y 4 (where n 0, 1 or 2), -SO 2 -HY 4 , NH-Y 4 , or N (Y 4 ) 2 , where Y 4 is H, phenyl (optionally one or more times halogen (in particular F) or if appropriate substituted fluorinated alkyl), or alkyl (wherein the alkyl group may be substituted with -OH, -COOK, and / or -NHCO-C ! -3 -alkyl, and wherein alkyl is preferably C1-3 alkyl);
  • R 3 particularly preferably being substituted by -OH, O-alkyl, SH, S-acyl, O-CO-alkyl, O-CO-NH-alkyl, NH-CO-alkyl, NH-CO-NH-alkyl, S (O) n -alkyl, S0 2 -NH-alkyl, NH-alkyl, N (alkyl) 2 , or NH 2 may be substituted (wherein alkyl is preferably Ci-3 alkyl); where n represents 0, I or 2,
  • R ' is H or F
  • 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 together represent (to form a pyrido ring) -CH 2 -CHR 11 - or -CHR 11 -CH 2 -, where R "is H, or R 4 -L- # l and R 2 is H;
  • A represents CO
  • R 3 ⁇ (CH 2 ) OH, -CH (CH 3 ) OH, -CH 2 SCH 2 CH (COOH) NHCOCH 3 , -CH (CH 3 ) OCH 3 , a phenyl group containing 1 -3 halogen atoms, 1- 3 amino groups or 1 -3 alkyl groups (which may be halogenated if necessary, or represents -L- # l,
  • R represents 5 or H
  • R ° and R 7 independently of one another represent H, Cw-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 ; H represents.
  • R ; H represents.
  • R represents -L- # 1, COOK or H
  • R 2 and R 4 are H or R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR "- or -CHR ! I -CH 2 -, where R i is H,
  • A represents CO
  • R 5 represents H
  • R ° and R 7 independently of one another represent H, Cu-alkyl or halogen, in particular that R 6 and R 'represent F;
  • R 8 is C 1-4 -alkyl (preferably tert-butyl).
  • R 9 represents H.
  • R 1 is H, -L-Binder, -MOD or - (CH 2 ) o- 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY'Y 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, H 2 , - (CH 2 CH 2 O) o-3- (CH 2 ) 0 -3Z '(for example - (CH 2 ) 0 - 3 Z'), or -CH (CH 2 W) Z ', and Y 3 represents H or - (CH 2 ) 0 ..
  • Z ' is H, NH 2 , SO 3 H, -COOH, -NH-CO-CH 2 - CH 2 -CH (NH 2 ) COOH or - ' O-Ni i-Ci IV ' ⁇ (() (II) where G represents H or OH, 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, where Y 4 is Imeares or branched, optionally substituted by-NHCO L, Ci-e 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 C M alkyl,
  • Z is -II, 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-: > Z ', and Y 3 is H or -
  • SG j ys represents a group cleavable by lysosomal enzymes, in particular a group consisting of a di- or tripeptide
  • R 4 ' is a C 1-6 -alkyl, C -wo-aryl- or cocooro-aralkyl-, C 5-10 -heteroalkyl -, Ci-io-alkyl-O-Cö-io-aryl, C5.10-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkoxy, Ci-io-alkoxy, Ce-io-aryloxy- or Ce-so-aralkoxy, Cs-io-heieroaralkoxy, G-lo-alkyl-O-Ce- 10-aryloxy, Cs-io-heterocycloalkoxy group which are mono- or polysubstituted by ⁇ NH 2 , - ⁇ - Alkyl, -N (alky
  • Y 1 and Y 2 independently of one another are H, NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is H or -
  • Y 4 is linear or branched, optionally substituted with-NHCONH 2 , 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 is linear or branched Cs-6 alkyl represents;
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR 'O- or -CHR I 0 -CH 2 -, wherein R 10 represents H, NH 2 , SO 3 H, COOH, SH, or OH;
  • A represents CO, SO, SO2, SO2NH or (NM!
  • R 3 represents -L-Binder, -MOD, or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, Heierocycloalkyl- group, preferably -L-BINDER or a Cno-alkyl, Ce-io-aryl - or Ce-io-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-O-Ce-io-aryl or Cs-io Heterocyclealkyl group containing 1 to 3 -OH groups, 1 to 3 halogen atoms, 1 to 3 halogenated alkyl groups (each having 1 to 3 halogeno moieties), 1 to 3-alkyl groups, 1 to 3-SH groups, and 3 -S-alkyl groups, 1 -3 -O-CO-alkyl groups, 1-3 -O-CO-NH-alkyl Grappen, 1-3 -NH-CO-al
  • alkyl is preferably Ci-io-alkyl
  • R 5 is H, H 2 , NO 2 , halogen (especially F, Cl, ⁇ r), -CM, CF 3 , -OCF 3 , -CH 2 F, -CH 2 F, SH or - (CH 2 ) O-3Z wherein Z is -FI, -OY 3 , -SY 3 , halogen, NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 , wherein Y 1 and Y 2 are independently H, NH 2 , or - represent (CH 2 3 ', and Y 3 represents H or - CC ' l I.) .. / ⁇ , wherein Z 'represents H, SO 3 H, NH 2 or COOH;
  • R 9 represents H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; where -MOD - ( NR10 ) r (G!) o -G2-G3, where
  • R represents H or C -C : -. ⁇ Il,>I;
  • G represents -NHCO- or -CONH- (wherein when G is -NHCO-, R '° is not NH 2 );
  • n 0 or 1
  • o 0 or 1
  • G2 is a straight-chain and / or branched hydrocarbon group having 1 to 10 carbon atoms which is mono- or polysubstituted by one or more of the groups -O-, -S-, - SO-, S0 2 , -R-, -RYCO-, CONRY-, -NR.YNRY-, -SO 2 ⁇ Ri ' NR ⁇ -. -CONRJ'NRy- (wherein R y II, phenyl, C j -CiQ-alkyl, C2-C
  • -COOH -OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid
  • group -MOD preferably has at least one group -COOH, and their salts, solvates, salts of solvates and epimers.
  • R 1 represents -L-BINDER, H, or - (CH 2 ) o- 3 Z, wherein Z is -H, -NHY 5 , -OY 3 , -SY 3 , halogen, -CO- ⁇ ' ⁇ 2 , or -CO Represents -OY 3 ,
  • Y 1 and Y 2 independently of one another are H, NFI 2, or -CH (CH 2 W) Z ', and Y 3 represents H or - (CH 2 ) o- 3 Z', wherein Z 'is H, NH 2 , SO 3 H, COOH, -NH-CO-CH 2 - ( ⁇ ! ⁇ ( ' !! ⁇ ⁇ ! ⁇ ) ( ⁇ () ()! I or - (CO-NH-CHY 4 ),.
  • Y represents H or OH, where Y 4 is linear or branched, optionally substituted by -NHCONtfc, Ci-eAJkyl or optionally substituted with -NH2 aryl or benzyl;
  • R 2 and R 4 are independently H, -SG lys - (CO) -R 0 4 ', -CO-CHY 4 -NHY 3 or - (CH 2) o-3Z ,, or R 1 and R 4 together ( to form a pyrrolidine ring) -CH 2 -CHR 11 - or - CHR i!
  • R 2 represents H, ⁇ CO-CHY 4 ⁇ NHY 5 or - (CH 2 V 3 Z and R 4 represents -L- # 1, where R 1! H, NH 2 , SO 3 H, COOK, SH, halogen (in particular F or CT), C M Alkyi, C1- 4 Haioalkyi, C i-4 is alkoxy, hydroxyl-substituted CwAlkyL COO (Ci-4 alkyl), or OH; wherein SG j y g represents a cleavable by enzymes lysosomaie group, in particular a group consisting of a di- or tripeptide, R 'is a C 1-10 -alkyl, C 3-10 -aryl or coco-aralkyl, C 5-10 -heteroalkyl-, C 1-10 heterocycloalkyl, heteroaryl, heteroaryl-alkyl, heteroaryl-alkoxy, C 1-10 -al
  • Y 1 and Y 2 are independently H, H 2 , or - (CH 2 V 3 Z ', and Y J H or -
  • Y 4 is linear or branched, optionally substituted with-NHCONH 2 , Ci- ⁇ 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 Ci-e represents alkyl;
  • a CO, SO, SO2, S -M! or CNNH 2 represents;
  • R J -L-BINDER or an optionally substituted alkyl, aryl, heteroaryl, heteroalkyl, represents heterocycloalkyl group is preferred; -L-BINDER or a CMO-alkyl, Ce-io-Ar l- or Ce-io-aralkyl, Cs-io-Heteroalkyi-, C 1.
  • io-alkyl-O-Ce-o-Aryi- or Cs-io-heterocycloalkyl-groups having 1 to 3 -OH groups, 1 to 3 halogen atoms, 1 to 3 halogenated alkyl groups (each having 1 to 3 halogen atoms), 1 to 3 O-alkyl groups, 1 to 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 (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 - (CH 2
  • Alkyi is preferably Cwo-alkyl
  • R 5 is H, F, NI-12, N0 2 , halogen, SH or -iCH), where 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 V 3 Z ', and Y 3 is H or - (CH 2 ) o -.3Z', where Z 'is H, SO 3 H, NH 2 or COOH;
  • L is a linker and BINDER for binder or derivative biei'von provides, where the binder may be bound to several drug molecules,
  • R 6 and R '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 or halogen,
  • R 5 represents (optionally fluorinated) C 1-10 -alkyl, (optionally fluorinated) Gt-io-cycloalkyl or optionally substituted oxetane;
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; and their salts, solvates, salts of solvates and epimers.
  • KSP inhibitor antibody conjugates are preferred according to the invention:
  • R 1 , R 2 , R 4 , R 3 , R 6 , R 7 , R 8 and R 9 have the same meaning as in formula (II) or (IIa),
  • A is CO
  • ⁇ is a single bond
  • -O- CH 2 represents - or --CH 2 -O-
  • R 20 represents H 2, F, CF 3, or CH 3
  • n represents 0, I, or 2.
  • R 1 , R 3 , R 6 , R 7 , R s , 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 1 represents -L B INDER
  • Formula (Iii) has:
  • R'-L- # l represents
  • A represents CO
  • R 6 , R 7 , R 8 and R 9 have the same meaning as in formula (I) have formula (ilk):
  • R -L- # l represents:
  • A is CO and R 3 (I i Oi i - represents;
  • R ', R 6 , R 7 , R 8 , and R 9 have the same meaning as in Formei (I).
  • Z represents Cl or Br;
  • R l is - (CH 2 ) o- 3 Z, where Z is COOH or -CO-NY'Y 2 , where Y 2 - (CH 2 CH 2 O
  • Y 1 represents H
  • Y 2 represents - (CftCftOyCifeCHbZ 'and Z' represents -COOH;
  • Y ! H represents Y 2 -CH 2 CH 2 Z 'and Z' ⁇ (CONHCFiY 4 ) 2 COOH;
  • Y 1 represents H
  • Y 2 represents -CH 2 CH 2 Z '
  • Z' - (CONHCHY 4 ) 2 represents COOH and represents Y * / -propyl and the other represents - (CH 2 ): t -NHCONH 2 ;
  • Y 1 represents H
  • Y 2 represents -CH 2 CH 2 Z '
  • Z' - (CONHCHY 4 ) 2 represents CQQH and one represents Y 4 -CH 3 and the other represents - (CH 2 ) 3 -NHCO II 2 ;
  • Y 4 is linear or branched, optionally substituted with -NHCONH 2, CM alkyl; at least one member of Y 4 is selected from z ' -propyi or -CH3.
  • Y 1 represents H
  • Y 2 represents -CH 2 CH 2 Z '
  • Z' represents -CONHCHY 4 COOH
  • Y optionally with
  • -NH 2 represents substituted aryl or benzyl
  • Y 4 represents aminobenzyl
  • R 2 represents (CH 2 ) o-3Z and Z represents -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 - H 2 ;
  • Y 4 is linear or branched, optionally substituted with -NHCONH 2 C 1-6 alkyl.
  • R ', R 2 or R' in formula (I) or (II) represents MOE
  • R 3 represents -MOD and R 1 or -L- # 1 and -L-Bf DER, respectively, where -MOD represents - (NR 10 ) ir ⁇ GI) o -G2-G3, wherein
  • R 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 12 -alkyl, C C 1 -C 4-alkenyl, or C 2 -C 1-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 is H, C 1 -C 3 -alkyl or phenyl) may be interrupted, wherein the hydrocarbon chain including the side chains, if may be substituted with -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid, wherein G3 is -H or -COOH, and wherein the grappe is -MOD preferably at least one group -COOH;
  • the group -MOD has a (preferably terminal) COOH Grappe, for example in a betaine group.
  • the Grappas -MOD the formula -CH2-S x - (CH 2) o - 4- CHY 5 -COOH, wherein x is 0 or 1, and Y 5 represents H or NHY 6, wherein Y6 is H or -GOCH -, represents.
  • Y 'and Y 2 independently of one another are H, NH 2 , or - (CH 2 CH 2 O) o- 3 - (CH 2 ) 0 , ⁇ ' or - CH (CH 2 W) Z ', and Y 3 H or - ⁇ U - ⁇ ⁇ /, where Z 'is H, Ni l; S0 3 H, COOH, - NH-CO-CH 2 -CH 2 -CH (NH 2 ) COOH or - (CO-NH-CHY 4 ), -3 COOH;
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 , or optionally substituted with -NH 2 substituted aryl or benzyl;
  • R 2 and R 4 are independently H
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR "- or -CHR 1 '- CH 2 -, where R H is H, NH 2 , SO 3 H, COOH, SH, halogen (especially F or Cl), C is Aikyl, Ci-4 haloalkyl, Ci- 4 alkoxy, hydroxyl-substituted Ci- 4 alkyl, COO (CM alkyl) or OH; wherein SG jvs represents a group which can be cleaved by lysosomal enzymes, in particular a group consisting of a di- or tripeptide, R 'is a CMO-alkyl, Cs-io-aryl or Ce-io-aralkyl-, C 5-10 -heteroalkyl- , C 1-10 Alk-O-Ce-io-Aiyl, C 5-10 heterocycloalkyl, heteroaryl, heteroary
  • Z represents -H, halogen, -OY 3 , -SY 3 , NEY 3 , -CO-NY ] Y 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 independently of one another are H, H 2 , or - (CH 2 V 3 Z ', and Y 3 H or -
  • Y 4 is linear or branched, optionally substituted with -NHCONH2, C1-6 alkyl or optionally with -NH2 substituted aryl or benzyl and Y 5 is H or -CO-CHY * -NH2, wherein Y * represents linear or branched CW alkyl ;
  • A represents CO, SO, SO 2, SO M l or C NH 2 ;
  • R 3 is -L-BTNDER, an optionally substituted alkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, or --- CH 2 -Sx- (CH 2 ) o- 4 -CHY s -COOH, where x 0 or 1, and Y s represents H or NHY 6 , where Y 6 is H or -COCH 3 .
  • Grappen 1 -3 -NH 2 groups or 1-3 - (CH 2 ) o- 3 Z ⁇ , wherein Z is -H, halogen, -OY 3 , -SY 3 , -NHY 3 , -CO- ⁇ ' ⁇ 2 , or -CO-OY 3 , with Y 'and Y independently of one another are H, NH 2 , or - (CH 2 ) 0 -3Z', and Y 'is H, - (CH 2 ) (w-CH (NHCOCH; ) Z 1, - (CH 2) o- 3 -CH (NH 2) Z 1, or - ⁇ ( ⁇ 1 ⁇ ), 7 represents: where Z 'is H, SO 3 H, NH 2 or COOH .
  • alkyl 'is preferably Cwo-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 , wherein Y 1 and Y 2 are independently H, NH 2, or - (CH 2 V 3 Z ', and Y 3 is H or - (CH 2 ) O-3Z', where Z 'is H, SO 3 H, NH 2 or COOH; stands for a linker and BINDER stands for the antibody, wherein the binder may possibly be bound to several active substance molecules,
  • R 6 and R 'independently of one another represent H, cyano, (optionally fluorinated) C 10 -alkyl, (optionally fluorinated) C 2-10 -alkenyl, (optionally fluorinated) C 2-10-alldnyl, hydroxyl or halogen,
  • R s represents (optionally fluorinated) C 1-10 -alkyl, (optionally fluorinated) C 1-10 -cycloalkyl or optionally substituted oxetane;
  • R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ; and their salts, solvates, salts of solvates and epimers.
  • Z represents Cl or Br
  • Y 1 is H
  • Y 2 is C 1 -C 8 C 1 -C 5 -CH bZ 'and Z' is -COOH;
  • Y 1 represents H
  • Y 2 represents -CH 2 CH 2 Z 'and Z 1 represents - (COi ⁇ HCHY 4 ) 2 COOH;
  • Y ! H represents, V - ⁇ ⁇ ⁇ ⁇ . /. ' represents, Z ' ⁇ (CONHCFIY 4 ) 2 COOH and represents a representative of Y 4 isopropyl and the other - (CH 2 vNHCONH 2 represents;
  • Y ! H represents Y 2 -CH 2 CH 2 Z ', Z' - (CONHCHY 4 ) 2 COOH and represents one representative of Y 4 - CH 3 and the other represents - (CH 2 ) 3 -NHCONH 2 ;
  • Y 4 is Cw alkyl, linear or branched, optionally substituted with -NHCONH 2; at least one member of Y 4 is selected from propyl or -CH 3.
  • Y ! H is H, Y 2 is -CH 2 CH 2 Z ', Z' is -CONHCHY 4 COOH and Y 4 is aryl or benzyl optionally substituted with -NH 2 ;
  • Y 4 represents an ammobenzyl
  • R 2 is - (CH 2 ) o-3Z and Z is -SY 3 ;
  • R 4 is -CO-CHY 4 -i ⁇ HY 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 C 1 -C 6 alkyl optionally substituted by -NHCONH 2 . Furthermore, preference is given to compounds of the formula (I), (Ia), (II), (IIa) or (III)
  • Y ! and Y 2 independently of one another are H, NH 2 , - (CH 2 CH 2 O) o-3- (CH 2 ) o-3Z '(for example - (CH 2 ) o-3Z 1 ), or -CH (CH 2 W) Z is Y, and Y 3 is H or - (CH 2 ) o-3Z ', where Z' is H, NH, SO 3 H, COOH, -NH 2 CO-CH 2 -CH 2 -CH (NH 2 ) COOH or (CO-NH-CHY) i -3 represents COOH; where represents WH or OH,
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 , Ci eAJkyl or optionally substituted with -NH 2 substituted Aiyl or Benzyi;
  • R 2 represents H, -CO-CHY 4 -NHY 5 or - (CH 2 ) Z,
  • Z is -II, 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 ) o-3Z ', and Y 3 is H or -
  • Z 1 represents H, SO 3 H, NH 2 or COOH
  • Y * independently of one another linear or branched, optionally with-NHCONH? substituted, Cw Aikyl or optionally substituted with -NH substituted Aiyl or Benzyi and Y S represents H or -CO-CHY * -NH 2 , wherein Y ° represents linear or branched CM Aikyl;
  • 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, SQ., SOzNH or CNNH 2 ;
  • R 3 represents -L-l or -L-BINDER, -MOD or an optionally substituted Aikyl-, cycloalkyl, aryl, heteroaryl, heteroalkyl, Heteroeycloalkyl- group, preferably a Ci-io Aikyl-, Ce -10-aryl or ceto-aralkyl, C 5-10 -heteroalkyl, ci-alkyl-O-ce-io-aryl or C 5-10 -heterocycloalkyl group 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-Aikyl groups, 1 -3 -O-CO-alkyl groups, 1-3 -O-CO-NH-alkyl groups, 1-3 -NH-CO-alkyl groups, 1-3 -NH-CO-
  • Z is -H, halogen, -OY 3 , -SY 3 , -NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 , with Y 'and Y 2 independently of one another H, NH 2 , or represents - (CH 2 ) o-3Z ', in which Y 3 H, - (CH 2 ) o-3-CH (NHCOCH 3) Z - (CH 2 ) o-3-CH (NH 2 ) Z' or - (CH 2 ) o-3Z 'wherein Z' may be H, SO 3 H, NH 2 or COOH (where "Aikyl” is preferably CWo-alkyl); R 5 H, -MOE), NH 2 , N0 2 , halogen (especially F, Cl, Br), -CN, CF 3 , -OCF 3 , -CH 2 F, -CH 2 F, SH or - (CH 2 )
  • Y 1 and Y 1 are independently H, NH 2 , or - (CH 2 V 3 Z ', and ⁇ ' is H or - ( ⁇ 2 ) ⁇ -: ⁇ , ⁇ ', where Z' is H, SO 3 H, NH 2 or COOH represents;
  • R 6 and R ' is independently H, cyano, (optionally fluorinated) Ci-10 alkyl, (optionally fluorinated) C2-10- alkenyl, (optionally fluorinated) C 2 _! O alkynyl, hydroxy, N0 2 , H 2 , COOH or halogen (especially F, Cl, Br),
  • R 8 (optionally fluorinated) O- io-alkyl, (optionally fluorinated) C 2 _! O-alkenyl, (optionally fluorinated) C 2 _! O-alkynyl, or (optionally fluorinated) Ci-io-cycloalkyl ; where one of the substituents R 1 and R 3 represents -L- # 1 or -L-BI DER,
  • R 9 is H, F, CHj, CF 3 , CH 2 F or CHF 2 ; where -MOD - ( NR10 ) ir ⁇ Gf) 0 -G2-G3, where
  • R 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 ⁇ -C j Q alkyl, C ⁇ -C j Q alkenyl, or C2-C1 Q represents -Aikinyl, each with
  • Y ! and Y 2 independently of one another are H, NH 2 , - (CH 2 CH 2 O) o-3- (CH 2 ) 0 -3Z 1 (e.g., - (CH 2 ) o- 3 Z '), or -CH (CH 2 W) Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', where Z 'is H, NH 2 , SO 3 H, COOH, -NH-CO-CH 2 » CH 2 » CH (NH 2 ) COOH or - (CO-NH-CHY 4 ) ,. 3 represents COOH; where represents WH or OH,
  • Y 4 is linear or branched, optionally with HCONH 2 substituted, Ci- ⁇ alkyl or optionally -NH 2 substituted aryl or benzyl;
  • R 2 is H, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 . 3 Z represents,
  • Z is -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 ,
  • ⁇ '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 -NHCONHo, Ci-e alkyl or optionally substituted with -NFI 2 substituted aryl or benzyl and Y s represents H or -CO-CHY 6 -NH 2 , wherein Y * linear or branched Ci -e is alkyl;
  • R 4 represents H
  • a CO, SO, SO 2 , SO M! or CNNH 2 represents;
  • R 3 represents -L- # l or -L-BTNDER, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably a CWo-alkyl, Ce-io -Aryl or Ce-io-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-O-Ce-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 -S-alkyl groups, 1 -3 -O- CO-alkyl groups, 1-3 -O-CO-NH-alkyl Grappen, 1-3 -NH-CO-alkyl groups
  • R 5 H, -MOE 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-3Z, wherein 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 J is H or - (CH 2 ) 0 - ;; Z', where Z 'is H, SO 3 H, NH 2 or COOH;
  • R 6 and R 'independently represent H or halogen (especially F, Cl, Br);
  • R ° is (optionally fluorinated) C 1-10 alkyl; where one of the substituents R ! and R 3 represents -L- # 1 or -L-BINDER, respectively,
  • R 9 represents H, F, CH- "CF 3 , CH 2 F or CHF 2 ; wherein -MOD is -CH 2 -Sx- (CH-CHY 5 -COOH on, wherein x is 0 or 1, and Y 5 is H or NHY 6 , wherein Y 6 is H or -COCH 3 , and their salts, solvates, salts the solvates and epimers.
  • R 1 and R 5 are H or -L- # 1;
  • R 2 and R 4 are H or R 1 and R 4 together (to form a pyrrolidine ring) -CH 2 - CHR ! 0 - or ⁇ CHR 10 -CH 2 -, where R ! 0 is H; and
  • R 3 is CTI 2 OH, CH (CH 3 ) OH or - L - # 1, wherein one of the substituents R 1 and R '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, 5-33 (2010)).
  • the in vivo cleavable linkers have an in vivo spaizeable group, which in turn can be distinguished between chemically in vivo cleavable and enzymatically in vivo cleavable groups.
  • “Chemically in vivo cleavable” or “enzymatically cleavable in vivo” means that the linkers or groups in the circulation are stable and only at or in the target line 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 A inal; the enzymatically in vivo cleavable groups are in particular 2-8-oligopeptide group, in particular a dipeptide group or glycosides.
  • Peptide cleavage sites are in Bioconjugate Chem. 2002, 13, 855-869, as well as Bioorganic & Mediana! Chemistry Edinburghs 8 (1998) 3341-3346 and Bioconjugate Chem. 1998, 9, 618-626. These include, for example, valine-alanine, valine-lysine, valm-citrulline, alanine-lysine and phenylalanine-lysine (possibly with additional amide group).
  • the in vivo stable linkers are characterized by high stability (less than 5% metabolites after 24 hours in plasma) and do not have the above-mentioned chemically or enzymatically in vivo cleavable groups.
  • the linker -L- preferably has one of the following basic structures (i) to (iv):
  • m 0 or 1
  • SG is a (chemically or enzymatically) in vivo cleavable group (especially disulfide, hydrazone, acetal, and aminal, or a protease cleavable 2-8 qigopeptide group)
  • SGI is an oligopeptide group or preferably a dipeptide group
  • LI independently for in vivo stand stable organic groups
  • L2 stands for a coupling group to the binder or a single bond. The coupling is preferably carried out on a cysteine residue or a lysine residue of the antibody.
  • the coupling may be to a tyrosine residue, glutamine residue or an unnatural amino acid of the antibody.
  • the unnatural amino acids may include, for example, aldehyde or keto groups (such as formyl glycine) or azide or alkyne groups (see Lan & Chin, Cellular incorporation of Unnatural Amino Acids and Bioorthogonal Labeling of Proteins, Chem. Rev. 2014, 114, 4764-4806 ).
  • the linker gamd structure (iii) is particularly preferred.
  • Administration of a conjugate of the invention having a linker structure (iii) and coupling of the linker to a cysteine or lysine residue of the antibody results in metabolism of cysteine or lysine derivatives of the following formulas:
  • each LI is bound to the low molecular weight KSP inhibitor, for example a compound of FoiTnel (I), (Ja), (II), (IIa), (IIb), (IIca), (IM), (Ile), ( Ilf), (III) or (IV).
  • Liiiker basic structure (i) when attached 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 suifhydryl compound to form a sulfide (e.g., thioether) or disulfide bridge.
  • Preferred are stable sulfide bridges. 1.2 is preferred
  • # 'de denotes the point of attachment to the sulfur atom of the antibody
  • # 2 denotes the point of attachment to the group V
  • R 2 represents COOK, 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 i0 represents H, NFI 2 or Ci-C, -alkyl
  • G represents -NHCO-, -CONH- or ⁇ /
  • (R 1U is preferably not Nt if Eq
  • n 0 or 1
  • 0 is 0 or 1
  • G 2 is a straight-chain 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 , - R> ' -, -
  • NHCONH 2 , -COOH, -OH, -I2, NH-CNNH2, sulfonamide, sulfo, suifoxide, or sulfonic acid), -CO-, -CR * N-O- (where Rx is H, Ci-C ⁇ -Alkyl or phenyl) and / or a 3 to 10-membered, aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from N, O and S, -SO- or -SO 2 - may be interrupted (preferably
  • hydrocarbon chain including the side chains, if present, may be substituted by -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNH 2 , sulfonamide, sulfone, suifoxide, or sulfonic acid.
  • G2 is a straight-chain or branched hydrocarbon chain having 1 to 300 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-, - ⁇ -, -SO 2 NHNH-, -CONHNH- and a 5 to
  • 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, suifoxide, or sulfonic acid may be substituted.
  • hydrocarbon chain including the side chains if present, with -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH2, sulfonamide, sulfonated, sulfoxide, or sulfonic acid may be substituted.
  • Rx is H, C j ⁇ -C alkyl or phenyl.
  • # '- is the binding to the KSP inhibitor and 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 cyclopean alkyl groups generally comprises an ⁇ , ⁇ -divalent alkyl radical with the respectively indicated number of carbon atoms.
  • Examples which may be mentioned by way of example and with preference are: methylene, ethane-1,2-diyl (1,2-ethylene), propane-1,3-diol (1,3-propylene), butane-1,4-diyl (1,4) Butylene), pentane-l, 5-diyl (1,5-pentylene), hexane-1, 6-diyi (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).
  • the Aikylengue in the hydrocarbon chain may also be branched, ie, one or more H atoms of the above linear Aikylengue may optionally be substituted by Cl-10-alkyl groups and thus form side chains.
  • the hydrocarbon chain can furthermore contain cyclic aikylene groups (cycloalkanediyl), for example 1,4-cyclohexanediyl or 1,3-cyclopentanediyl. These cyclic groups can be unsaturated.
  • aromatic groups arylene groups
  • one or more H atoms may optionally be substituted by C 1-10 -alkyl groups. It is thus formed a Kohienwasserstofflcette, which is possibly 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 can, if present, with -NHCONH 2 , -COOK, -OH, -NB 2 , NH-C H 2 ,
  • the hydrocarbon chain may be mono- or polysubstituted, identically or differently, 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 1 O-linked, 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:
  • ⁇ represents the binding to the Bmderpeptid or -protem
  • LI has the Fonnei ⁇ NR * ⁇ B-, where
  • H oilcr Ni l represents
  • B represents - [(CH 2 x - (X 4 ) y ] w - (CH 2 ), -
  • Preferred linkers L according to the invention have 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-,
  • 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 Antiköiper. 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
  • Aryl groups and / or straight-chain and / or cyclic Aikylengue which is mono- or polysubstituted by one or more of the groups -O-, -S-, -SO-, SO 2, -NH-, -CO-, -NHCO-, - CONH -, -NMe, -NHNH-, -SO2 HNH-, -CONHNH- and a 3 to 10-membered (preferably 5 to 10-membered), aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from N, O and S, -SO - or -SO 2 - may be interrupted, wherein the side chains, if present, with -NHCONH 2 , -COOH, -OH, -NH 2 , NH-CNNH 2 , sulfonamide, sulfone, suifoxide or sulfonic acid may be substituted.
  • n 1;
  • n 0;
  • o 0 or 1
  • s, t, v and w are each independently 0 to 20, and u is 0 or 1.
  • Preferred groups LI in the above formula ⁇ - (CO) m-L1-L2- ⁇ are the following, wherein each r independently of one another is a number from 0 to 20, preferably from 0 to 15, particularly preferably from 1 to 20, in particular preferably from 2 to 10:
  • linkers LI indicated in these lines are linked to a linker L2 which is selected from:
  • the bonds to a cysteine residue of the binder are preferably more than 80%, more preferably more than 90% (in each case based on the total number of bonds of the linker to the binder), particularly preferably in one of the two structures of the formula A7 or A8 before.
  • the structures of the formula A7 or A8 are generally present together, preferably in a ratio of 60:40 to 40:60, based on the number of bonds to the binder. The remaining bonds are then in the structure
  • L2 can also be a Stnikiur L2 of the following formula:
  • conjugates with corresponding linkers have the following structures, wherein XI is CH, X2 C, and X3 N, and LI has the meaning given above, L2 and L3 has the same meaning as LI, AK1 stands for an (anti ⁇ B7H3 antibody Preferably, AK1 is a human, humanized or chimeric monoclonal antibody or an antigen-binding fragment thereof.
  • AK1 is an aglycosylated anti-B7FI3 antibody that is linked to a cysteine residue and n is a number from 1 to 10 specifically binds the human Ig4 and / or the human and / or murine Ig2 isoform of B7H3, in particular the anti-B7F6 antibody TPP-5706 and its humanized variants such as TPP-6642 and TPP-6850.
  • 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 Binderpepüd 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 by one or more of the groups -O-, -S-, -SO-, SO 2 , -NH-, -CO-, -NHCO-, -CONH-, -NMe-, - ⁇ - , -SO2NHNH-, -CONHNH- and a 5- to 10-membered, aromatic or non-aromatic Heierozyklus with up to 4 heteroatoms selected from N, O and S, -SO- or -S02- may be interrupted, wherein the side chains, if may be substituted with -NHCONH 2 , -COOK, -OH, -ML, NH-CNNfL,
  • 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.
  • Particularly preferred is an aglycosylated anti-B7H3 antibody which specifically binds the human 4Tg isoform, in particular the anti-B7H3 antibody TPP-5706 and its humanized variants such as TPP-6642 and TPP-6850.
  • SGI or SG is particularly preferred
  • XH a Ci-io-Alkylgnippe, which may optionally be substituted with - HCO th, -COOH, -OH, H2, NH-C H2, or sulfoacid.
  • 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 may be wholly or partly also in the form of the hydrolyzed open-chain succinic acid amide, as described above.
  • conjugates having the basic structure (i) have the following structure, where XI is CH, X2C, and X3 is N, L4 has the same meaning as LI, AK1 is an antit-B7H3 antibody linked via a C-block residue is, and n is a number from 1 to 10.
  • the antibody is preferably an aglycosylated human, humanized or chimeric anti-B7H3 monoclonal antibody or antigen-binding fragment thereof.
  • an anti-B7H3 antibody which specifically binds the human 4Ig isoform, in particular the anti-B7H3 antibody TPP-5706 and its humanized variants such as TPP-6642 and TPP-6850.
  • the conjugates according to the invention are prepared by initially providing the low molecular weight KSP inhibitor with a linker. Since so received Intermedia !; 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 by Ci-Ce alkoxy or -OH-substituted Ci- C 6 alkyl, and
  • XI CH, X2 C, and X3 is N, SG I, 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:
  • suceinimide-linked ADCs can be converted into the open-chain succinic acid amides after conjugation, which have a favorable stability profile.
  • This reaction can be carried out at pH 7.5 to 9, preferably at pH 8, at a temperature of 25 ° C to 37 ° C, e.g. by stirring.
  • the preferred stirring time is 8 to 30 hours.
  • 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.
  • AKl is an anti-B7H3 antibody linked via a cysteine residue or an antigen-binding fragment thereof
  • AK2 is one via a Lysine residue-coupled anti-B7H3 antibody or an antigen-binding fragment thereof.
  • AK1 and AK2 are aglycosylated anti-B 7H3 antibodies.
  • AK1 and AK2 is an anti-B 7H3 antibody that specifically binds the human 4Ig isoform, particularly the anti-B7H3 antibody TPP-5706 and its humanized variants such as TPP-6642 and TPP-6850.
  • the antibody is preferably an aglycosylated human, humanized or chimeric anti-B7H3 monoclonal antibody or an accessory-binding fragment thereof.
  • an anti-B7H3 antibody or an antigen-binding fragment thereof which specifically binds the human 4Ig isoform, particularly the anti-B7H3 antibody TPP-5706 and its humanized variants such as TPP-6642 and TPP-6850 Aglycosyl or aglycosylated antibodies do not contain any glycans at the conserved N-binding site in the CH2 domain of the Fc region.
  • Various possibilities of covalent coupling (conjugation) of organic molecules to antibodies are known from the literature.
  • the conjugation of the toxophore to the antibody via one or more Sehwefelatome of cysteine residues of the antibody and / or one or more NH groups of lysine residues of the antibody is preferred.
  • the antibody can be linked via a linkage with the linker.
  • the linkage of the antibody can be effected by means of a heteroatom of the binder.
  • Heteroatoms of the invention that can be used for linking are sulfur (in one embodiment via a sulfhydryl group of the antibody), oxygen (according to the invention by means of a carboxyl or hydroxyl group of the antibody) and nitrogen (in one embodiment via a primary or secondary amine group or Amidgatppe 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 Zielmoiekül.
  • the linkage has no influence on the binding activity of the antibody to the target molecule.
  • antibody is understood in its broadest sense according to the present invention and includes immunoglobulin molecules, for example intact or modified monoclonal antibodies, polyclonal antibodies or multispecific antibodies ⁇ eg bispecific antibodies).
  • 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).
  • Each VH and VL region typically consists of three CDRs and up to four FRs. For example, from the amino-terminus to the carboxy-terminus in the following order FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • An antibody can be obtained from any suitable species, eg, rabbit, llama, camel, mouse, or rat. In one embodiment, the antibody is of human or murine origin.
  • an antibody can be human, humanized or chimeric.
  • monoclonal antibody refers to antibodies obtained from a population of substantially homogeneous antibodies, ie, individual antibodies of the population are identical except for naturally occurring mutations which may occur in small numbers.Monoclonal antibodies recognize with high specificity a single antigenic binding site The term monoclonal antibody does not refer to a particular manufacturing process.
  • the term "intact" antibody refers to antibodies comprising both an antigen-binding domain and the light and heavy chain constant domain
  • the constant domain may be a naturally occurring domain, or a variant thereof in which multiple amino acid positions are altered were.
  • modified intact antibody refers to intact antibodies that have been fused to another polypeptide or protein that does not harbor an antibody via its amino terminus or carboxy-terminus via a covalent bond (eg, a peptide linkage) modified reactive cysteines are introduced at defined sites to facilitate coupling to a toxophore (see Junutula et al., Nat Biotechnol., 2008 Aug; 26 ⁇ 8): 925 ⁇ 32).
  • 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 parts or in full as a whole from synthetic sequences found in the United States of America Analysis of human antibody sequences.
  • a human antibody may be encoded by a nucleic acid isolated from a library of antibody sequences of human origin. An example of such antibodies is in Söderlind et al, Nature Biotech. 2000, 18: 853-856.
  • humanized or “chimeric” antibody describes antibodies consisting of a non-human and a human sequence portion. In these antibodies, part of the sequences of the human immunoglobulin (recipient) is replaced by sequence portions of a non-human immunoglobulin (donor).
  • the donor is a murine immunoglobulin in many cases.
  • amino acids of the CDR of the recipient are replaced with amino acids of the donor. Sometimes amino acids of the framework are replaced by corresponding amino acids of the donor.
  • the humanized antibody contains amino acids that were not contained in either the recipient or the donor and that were inserted during optimization of the antibody.
  • the variable domains of the donor immunoglobulin are fused to the constant regions of a human antibody.
  • 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 include amino acids as defined by Rabat and or amino acids of a hypervariable loop defined by Chotia.
  • the Rabat definition includes 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 (CDR3), 50-65 (CDR2 ) and 95-302 (CDR3) of variable heavy rescue (Rabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD. (1991)).
  • the definition according to Chotia includes 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).
  • a CDR may comprise amino acids from a CDR region as defined by Rabat and Chotia.
  • antibodies can be divided into different classes. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG and IgM, several of which can be broken down into other subclasses. (Isotypes), eg IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2.
  • the heavy chain constant domain corresponding to the different classes are referred to as [aipha / a], [delta / ⁇ ], [epsilon / ⁇ ], [gamma / y] and [my / ⁇ ]. Both the three-dimensional structure and the subunit structure of antibodies are known.
  • the term "functional fragment” or "antigen binding antibody probe” of an antibody / immunoglobulin is defined as a fragment of an antibody / immunoglobulin (e.g., the variable domains of an IgG) which still comprises the antigen binding domains of the antibody / immunoglobulin.
  • the "antigen binding domain" of an antibody typically comprises one or more hypervariable regions of an antibody, eg the CDR, CDR2 and / or CDR3 region
  • the "framework” or “framework” region of an antibody may also bind to the antibody
  • the antigen binding domain comprises at least amino acids 4 to 103 of the variable light chain and amino acids 5 to 109 of the variable heavy chain, more preferably amino acids 3 to 107 of the variable light chain Chain and 4 to 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 3 13 of the VH (numbering according to WO97 / 08320).
  • “Functional fragments” or “antigen-binding antibody fragments” of the invention do not exhaustively include Fab, Fab ', F (ab') /: and Fv fragments, diabodies, single domain antibodies (DAbs), linearae antibodies, single chain antibodies (single-chain Fv, abbreviated to seFv); and multispecific, such as bi- and tri-specific, antibodies formed from CA K Borrebaeck, editor (3995) Antibody Engineering (Breakthroughs in Molecular Biology), Oxford University Press; R. Kontermann & S. Duebel, editors (2001) Antibody Engineering (Springer Laboratory Manual), Springer Verlag). Antibodies other than "multi-specific” or “multi-functional” are those with identical binding sites.
  • Multispecific antibodies may be specific for different epitopes of an antigen or specific for epitopes of more than one antigen (see, for example, WO 93/17715, WO 92/08802, WO 91/00360, WO 92/05793, Tutt, et al., 1993 , J. Immunol., 147: 60 69; U.S. Patent Nos. 4,474,893; 4,7 14,68 1; 4,925,648; 5,573,920; 5,601,819; or Kostelny et al., 1992, J. Immunol. 148: 1547 1553 ).
  • An F (ab ') 2 or Fab molecule can be designed to reduce or completely prevent the number of intermolecular disulfide interactions that occur between the Chi and CL domains.
  • Epitopic determinants refers to protein determinants that can specifically bind to an immunoglobulin or T cell receptor
  • Epitopic determinants typically consist of chemically active surface groups of molecules such as amino acids or 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 polypeptide or protein other than an antibody 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 (Kohler 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., Mefh Enzymol., 92, 3-16, and Cabilly et al., US 4,816,567 or Boss et al US 4,816,397).
  • Antibodies of the invention can be obtained from recombinant antibody libraries, e.g. Based on the amino acid sequences of a variety of antibodies that Wuixien created 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.
  • 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 which has been purified to more than 95% by weight, based on the antibody or binder (determined, for example, by Lowry method, UV is spectroscopy or by SDS capillary gel electrophoresis) an antibody which has been purified to such an extent that at least 15 amino acids of the amino terminus or internal amino acid sequence can be determined or purified to homogeneity, homogeneity being determined by SDS-PAGE under reducing or non-reducing conditions (detection may be by Coomassie Blue staining or preferably determined by silver staining).
  • an antibody is usually produced by one or more purification steps.
  • the term "specific binding” or “specific binding” refers to an antibody or binder that binds to a predetermined antigen / target molecule.
  • Specific binding of an antibody or binder typically describes an antibody or binder having an affinity of at least 10 " M (as the Kd value, that is, preferably those having smaller Kd values than 10 " M), wherein the antibody or binder has at least one has two fold higher affinity for the predetermined antigen / target molecule than for a nonspecific antigen / target molecule (eg, bovine serum albumin, or casein) which is not the predetermined antigen / target molecule or a closely related antigen / target molecule
  • the antibodies preferably have an affinity of at least 10 '' 'M (as Kd value, so preferably those with smaller Kd values than 10' '' M), preferably of at least 10 " ⁇ M, particularly preferably in the range of 10" ⁇ M to 10 " ⁇ M up.
  • the Kd values can be determined by, for example, surface plasm
  • the antibody-antibody conjugates according to the invention likewise have affinities in these regions.
  • the conjugation of the active ingredients preferably does not significantly affect the affinity (as a rule, the affinity is reduced by less than an order of magnitude, ie, for example, 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 at least a factor of 2, preferably a factor of 5 or more preferably a factor of 10 than of an independent other antigen, e.g. human serum albumin (the affinity can be determined, for example, by surface plasmon resonance spectroscopy).
  • the antibodies used according to the invention are preferably cross-reactive.
  • the antibody used according to the invention binds not only the human target protein but also in the species used for the studies the species target protein binds.
  • the erfindöigsgeinäß used Antiköiper 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).
  • antibodies used according to the invention which are at least cross-reactive with the mouse target protein in addition to the human target protein. Preference is given to cross-reactive antibodies whose affinity for the target protein of the further non-human species does not differ by more than a factor of 50, in particular not more than a factor of ten, from the affinity for the human target protein.
  • the target molecule against which the binder e.g. an antibody or antigen-binding fragment thereof, a cancer target molecule.
  • target cancer 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 present on one or more cancer cell types compared to non-cancer 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.
  • extracellular cancer target molecule B7H3 SEQ ID NO: Q5ZPR3 (protein); SEQ ID NO: 80381 (DNA).
  • Antibodies that bind cancer targeting molecules can be prepared by those of ordinary skill in the art by known methods such as chemical synthesis or recombinant expression. Cancer target binders can be purchased commercially or can be prepared by one of ordinary skill in the art by known methods such as chemical synthesis or recombinant expression. Further methods for producing antibodies or antigen-binding antibody fragments are described in WO 2007/070538 (see page 22 "Antibodies"). The person skilled in the art knows methods such as so-called phage display libraries (eg Morphosys HuCAL Gold) and can be used to detect antibodies or antigen-binding antibody fragments (see WO 2007/070538, page 24 ff and AK example 1 on page 70, AK example 2 on page 72).
  • phage display libraries eg Morphosys HuCAL Gold
  • the antibodies of the invention are glycosylated or aglycosylated, i. in the latter case, they have no glycans on the conserved N-bonding moieties in the CH2 domain of the Fc region.
  • an anti-B7H3 antibody or an antigen-binding fragment thereof is used, preferably TPP5706 or an antibody derived therefrom.
  • TPP5706 or an antibody derived therefrom antibodies which bind to B7H3
  • EP2121008 describes the anti-B7H3 antibody 8H9 and its CDR sequences.
  • TPP3803 contains these CDR sequences in the context of a human IgOl.
  • the invention relates to conjugates with antibodies or antigen-binding antibody fragments thereof or variants thereof which have the following properties: specific 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 according to the invention bind to epitopes which are particularly suitable for internalization after binding.
  • the antibodies according to the invention are distinguished by a low immunogenicity when used in humans, which is achieved by extensive homology in the amino acid sequence of the antibodies according to the invention with the corresponding human germ line sequences.
  • Anti-B7H3 antibodies are described in the relevant literature, eg US 6965018 discloses the murine anti-B7H3 antibody secreted by the hybridoma PTA-4058. We determined the amino acid sequence of this antibody using standard methods.
  • TPP5706 is the chimera of murine Fv derived from this antibody with the Chl-Ch3 region of a human IgG1. The corresponding DNA sequences were inserted into a mammalian IgG expression vector and expressed as full-length TgGs. For example, 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, Biblio Publishing Ltd, 2007.
  • the antibody was 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. Furthermore, the potency of drug conjugates with TPP5706 was tested in vitro and in vivo as described in Examples C1, C-2 and C-6. In the course of the subsequent humanization of the binding agent several humanized derivatives of TPP5706 were identified, in particular TPP6642 and TPP6850, such as in AK Example 1 described. In these antibodies, the murine sequences are largely replaced by human sequences without significantly altering the B7H3 binding properties. A comparison of the amino acid sequences of these antibodies with common human germ line sequences further identified a series of amino acid substitutions containing a To increase the degree of homology between these antibodies and the human germ line sequences.
  • anti-B7H3 antibodies in this application are referred to the following preferred antibodies as shown in the following table: TPP-5706, TPP-6642, TPP-6850 and TPP-3803.
  • TPP-5706 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-6642 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-6850 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-3803 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-5706 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-6642 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-6850 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-3803 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.
  • 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: 41 represents the amino acid sequence of the extracellular domain of the human B7H3 polypeptide.
  • An antibody or antigen binding fragment which binds to B7H3 comprising: a variable heavy chain comprising the CDR1 heavy chain variable sequence as represented by SEQ ID NO: 2, the heavy chain CDR2 variable sequence as shown by SEQ ID NO: 3 and the heavy chain CDR3 variable 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 CDR2 variable A light chain sequence represented by SEQ ID NO: 7 and the light chain variable CDR3 sequence represented by SEQ TD NO: 8, or a variable heavy chain comprising the variable CDR1 heavy chain sequence as represented by SEQ ID NO:
  • Figure 12 shows 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 comprising light chain variable CDR1 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 SEQ ID
  • the antibody or anti-gene binding fragment thereof according to Embodiment 4 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 variable sequence of the light chain A chain as represented by SEQ ID NO: 15 or a heavy chain variable sequence as represented by SEQ ID NO: 21, and 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.
  • he antibody according to any one of the preceding embodiments 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 heavy chain sequence 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 as represented by SEQ ID NO Figure 3, or a heavy chain sequence as represented by SEQ ID NO: 39, and a light chain sequence as represented by SEQ ID NO: 4ö.
  • the antibody according to any one of the preceding embodiments, wherein the anti-B7H3 antibody is a humanized variant of one of the antibodies TPP6642 and TPP6850.
  • he antibody according to any one of the preceding embodiments comprising: a heavy chain sequence as represented by SEQ ID NO: 19 containing at least one amino acid substitution selected from a group containing the substitutions BIS, N33Y, V34M, T50I, F52N, G54S, N55G, D57S, N61A, K65Q, D66G, K67R, T72R, A79V and a light chain sequence as represented by SEQ ID NO: 20 containing at least one amino acid substitution selected from a group containing the substitutions E27Q, N28S, N30S, N31 S, T34N, F36Y, Q40P, S43A, Q45K, H50A, K52S, T53S, A55Q, E56S, H90Q, H91S, G93S, P96L, or a heavy chain sequence as represented by SEQ ID NO: 29 which is at least contains an amino acid substitution selected from a group containing the substitutions 13 IS, N33G, V34I, H35
  • the antibody according to any one of the preceding embodiments which is an IgO antibody.
  • 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 antibody or antigen binding fragment according to any one of the preceding claims which is a human, humanized or chimeric antibody or an antigen binding fragment.
  • the subject matter of the present invention accordingly also comprises the humanized derivatives TPP6642 and TPP6850 having the following amino acid substitutions, wherein E27Q is a substitution of E by Q at amino acid position 27 of the respective chain of the respective humanized derivative, N28S means a substitution of N by S at position 28 of the respective chain of the respective humanized derivative, etc.
  • TPP6642 light chain E27Q, N28S, N30S, N31S, T34N, F36Y, Q40P, S43A,
  • the present invention also encompasses all suitable isotopic variants of the compounds according to 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 reactive with another atom of the same atomic number but with a different atomic mass usually or predominantly occurring in nature atomic mass is exchanged.
  • 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 ⁇ (deuterium), J H (tritium), 13 C , l4 C, l7 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 CL S2 Br, 123 I, m l, i29 I and , 3, I.
  • Certain isotopic variants of a compound according to the invention may be useful, for example for the investigation of the mode of action or distribution of active substance in the body, due to the comparatively easy manufacturing and
  • the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as, for example, Det- or 1 CC- isotope-labeled compounds for example, an extension of the half-life in the body or a reduction of 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 methods known to the person skilled in the art, for example by the methods described below and the instructions given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • Salts 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 which can be used, for example, for the isolation or purification of the compounds according to 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, Naphthalttensulfonklare, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, ⁇ pfeiklare, citric acid, fumaric acid, maleic acid and benzoic 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 from 1 to 16 carbon atoms, as exemplified and preferably, ethylamine, diethylarain, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylpiperidine, ⁇ -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
  • 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 in which coordination with water occurs. 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 may themselves be biologically active or inactive, but are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).
  • Special Ausfiihmngsformen
  • KSP-L- is a compound of the following formula (I), (Ia), (II), (IIa), (IIb), (IIc), (IId), (Ile) (III), (IIj), (Ilk) or the following formula (Ilf)
  • the binder is an antkB7H3 antibody, which is preferably aglycosylated.
  • an anti-B7H3 antibody which specifically binds the human Ig4 and / or human and / or murine Ig2 isoform of B7H3, in particular the anti-B7H3 antibody TPP-5706 and its humanized variants such as TPP-6642 and TPP 6850th where n is a number from 1 to 10:
  • a ⁇ ( ⁇ : «:)) ⁇ is;
  • O-CO-NH-alkyl, NH-CO-alkyl, NH-CO-NH-alkyl, S (0> alkyl, S0 2 -NH-alkyl, NH-alkyl, N (alkyl) 2 , or NH 2 substituted may be (wherein alkyl is preferably C1.3 alkyl);
  • R 5 is H or F
  • R ° represents and R 'are independently H, (optionally fluorinated) Ci.3- alkyl, (optionally fluorinated) C2 .4 alkenyl, (optionally fluorinated) C2 -4 alkynyl, hydroxy or halogen;
  • R s is a branched Ci -s-alkyl group
  • R 9 is H or F, wherein one of the substituents R ] 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
  • # ' identifies the point of attachment to the optic nerve of the antibody, # 2 the point of attachment to the group L ! and LI through the formula
  • G l represents -NHCO- or ⁇ whil /;
  • n 0 or 1
  • o 0 or 1
  • G2 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms from aryl group. and / or straight-chain and / or branched and / or cyclic alkylene groups which are monosubstituted or polysubstituted by one or more of the groups -O-, -S-, -SO-, SO 2, -NH-, -CO-, -NHCO- , -CONH-, -NMe-, -NHNH-, -SO 2 NHNH-, -CO HNH- and a 3 to 10-membered, aromatic or non-aromatic heterocycle having up to 4 heteroatoms
  • N, O and S, or -SO- may be interrupted (preferably ⁇ /), wherein the side chains, if present, with - may be substituted HCONH2, -COOH, -OH, -NH 2, NH-CNNH2, sulfonamide, sulfone, Suifoxid, or sulfonic acid.
  • # 1 is the binding to the KSP inhibitor and the binding to the coupling group to the antibody (e.g., L2).
  • KSP-L- is a compound represented by the following formula (1), (Ia), (II), (IIa), (IIb), (ITc), (TTd), (ITe), (Iii), (IIj) (Ilk), (Iii) or the following formula (II ' g) or the following formula (Ilg), the binder is an anti-B7H3 antibody, which is preferably aglycosylated.
  • an anti-B7H3 antibody which specifically binds the human Ig4 and / or the human and / or murine Ig2 isoform of B7H3, in particular the anü-B7H3 antibody TPP-5706 and its humanized variants such as TPP 6642 and TPP-6850, where n is a number from 1 to 10:
  • A is CO (carbonyl); R 1 -L- # i, H, -COOK, -CONHNH 2, - (CH 2 ) i-3NH 2 , -CONZ "(CH 2 ) i-3 H 2 and ⁇ -CONZ" CH 2 COOH, where Z is "H or NH 2 ;
  • R 2 and R 4 are H, or R 2 and R 4 together (to form a pyrrolidine ring) -CH 2 -CHR I! - or -CHR n -CH 2 -, where R 10 is H;
  • R 5 is H or F
  • R 6 and R 7 are independently H, (optionally fluorinated) Ci-3-AlkyI (if any fl510riert.es) C 2 -4 alkenyl, (optionally fluorinated) C2 -4 alkynyl, hydroxy or halogen ;
  • R 8 is a branched C s -alkyl group
  • R 9 is H or F, wherein one of the substituents R 1 and R 'represents L-L, and
  • L represents the linker and #i represents the binding to the antibody
  • n 0 or 1
  • ⁇ represents the binding to KSP
  • ⁇ represents the binding to the antibody
  • # ' identifies the point of attachment to the optic nerve of the antibody, # 2 the point of attachment to the group L ! and LI through the formula
  • R 10 H, N li; or C 1 -C 3 alkyl
  • G represents -NHCO- or ⁇ whil /;
  • 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 group. 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-, -CO HNH-, and a 3 to 10-membered, aromatic or non-aromatic heterocycle containing up to 4 heteroatoms
  • N, O and S, or -SO- may be interrupted (preferably ⁇ /), wherein the side chains, if present, with - may be substituted HCONH2, -COOH, -OH, -NH 2, NH-CNNH2, sulfonamide, sulfone, Suifoxid, or sulfonic acid,
  • KSP-L- is a compound represented by the following formula (II), (IIa), (IIb), (IIc), (Ild), (Ile), (Iii), (IIg) (Iii), (IIj), ( Ilk) or the following formula (IIh), the binder is an aglycosylated anti-B7H3 antibody, and n is a number from 1 to 10:
  • R 2 and R 4 are H, or R 2 and R 4 together represent (without formation of a pyrrolidine ring) -CH 2 -CHR 11 - or -CHR "-CH 2 -, wherein R 1 represents H;
  • R 3 is a CMO-alkyl, which optionally with -OH, O-alkyl, SH, S-alkyl, O-CO-alkyl, O-CO-NH-alkyl, NH-CO-alkyl, Ni l -Cu- NH - ⁇ ikyl.
  • S (O) n -alkyl, S0 2 -NH-alkyl, NH-alkyl, N (aikyl) 2 , or NH 2 may be substituted (wherein alkyl is preferably C1-3 alkyl), or -MOD;
  • R ! 0 is H or C 1 -C 3 -alkyl
  • Gl represents -NHCO- or -CONH- (wherein when Gl -NHCO-, R i0 not NH 2);
  • n 0 or 1
  • o 0 or 1
  • G 2 is a straight-chain and / or branched hydrocarbon group having 1 to 10 carbon atoms which is mono- or polysubstituted by one or more of the groups -O-, -S-, -
  • R 5 is H or F
  • R represents H, (optionally fluorinated) Ci-3-alkyl, (optionally fluorinated) C2-4 alkenyl, (optionally fluorinated) C2 4 alkynyl, hydroxyl or halogen ° and R 'independently of one another;
  • R s is a branched Ci-s-alkyl group
  • R 9 is H or F, where -L is the linker and # 1 is the bond to the antibody, where -L- is represented by
  • 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'
  • LI represents the formula
  • R 10 is H, NH 2 or C 1 -C 3 alkyl
  • G represents -NHCO- or ⁇ whil /;
  • n 0 or 1
  • S02- may be interrupted (preferably ⁇ /), it being possible for hydrocarbon chain, including the side chains, if present, to be substituted by -NHCONH 2, -COOH, -OH, -NH 2 , NH-CNNH 2, sulfonamide, sulfone, sulfoxide or sulfonic acid,
  • the invention also provides binder-drug conjugates of the following general formula:
  • m is the number of drug molecules per linker and n is an average of the number of drug-Lmker conjugates per BINDER. The sum of all WS present in a conjugate molecule is thus the product of m and n.
  • WS is an active substance which shows therapeutic effect in animals, preferably humans, a local or systemic effect. These agents usually have a molecular weight of below 5 kDa, preferably below 1.5 kDa.
  • Preferred active ingredients are vinca alkaloids, Auristatme, tubulysins, duoearmycins, kinase inhibitors, MEK inhibitors and KSP inhibitors.
  • Formula A4 where # 'denotes the point of attachment to the sulfur atom of the binder, # 2 denotes the linking parts with the active substance, x represents 1 or 2, and R ⁇ COOH, COOK, COR (with R in each case Cl-3-alkyl), CONH2 , Br, preferably COOH represents.
  • LI has the same meaning as above.
  • -Ll - # 2 is represented by the following formula:
  • # 3 denotes the linking parts with the nitrogen atom
  • G is -NHCO- -CONH- or represents; (where if Gl NHCO or
  • n 0 or 1
  • o 0 or 1
  • G 2 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms from aryl 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, -NR>'-, - NRYCO-, -C (H) NRy-, -CONRY-, -NRYNRY-, -SO 2 NR NR v -, -CO RYNRY-, (wherein R y is H, phenyl, ci- CiQ-alkyl, C2-Ci0-alkenyl, or C2-C1 represents g-alkynyl, which may be substituted in each case with NHCONH 2 , -COOK, -OH, -NH2, NH-CNNH 2 , sulfonamide, sulfone, sulfox
  • hydrocarbon chain including the side chains if present, with -NHCONH 2 , -COOK, -OH, -NH 2 , NH-CN H 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted.
  • the bonds to a cysteine residue of the antibody Hegen are preferably more than 80%, more preferably more than 90%, particularly preferably (based on the total number of linker bonds to the antibody). in one of the two structures of formula A3 or A4.
  • conjugates with the linkers of the formula A3 or A4 can be obtained by coupling the antibodies to the corresponding bromo derivatives of the following formulas A3 'or A4':
  • bromo derivatives of the formula A3 'or A4' can be obtained by reaction of HOOCCH 2 CHBrCOOR 2 2 or HOOCCHBrCH 2 COOR 2 2 with an amine group of the binder, as exemplified in the following Schemes 30 to 32.
  • the invention also provides binder-drug conjugates of the following general formula:
  • m is a number from 1 to 2, preferably 1
  • n is a number from 1 to 50, preferably 1.2 to 20 and more preferably 2 to 8, wherein L has one of the following structures.
  • M is the number of drug molecules per linker and n is an average of the number of drug-linker conjugates per BINDER. The sum of all WS present in a conjugate molecule is thus the product of m and n.
  • active ingredient-antibody conjugates containing more than one drug molecule WS per drug-antibody conjugate, both structures according to the formulas AI and / or A2 in an active ingredient-antibody conjugate; available. Since it is in the inventive It is also possible for active ingredient-antibody conjugates to be a mixture of different active ingredient-antibody conjugates, that in this mixture are contained active ingredient-antibody conjugates both with the formula AI or formula A2 and with the formula AI and A2.
  • X represents a 5- or 6-membered, aromatic or non-aromatic heterocycle or homocycle, preferably -C H4- or -
  • R 1 represents an acid group, preferably -COOH or SO 3 H, selected from -CONH-, -OCONH-, -NHCO-, -NHCOO-, where r is 1, 2 or 3.
  • L ? is a bond or a group selected from a straight-chain or branched hydrocarbon chain having 1 to 100 (preferably 1 to 10) carbon atoms of arylene groups and / or straight-chain and / or branched and / or cyclic alkylene groups which is mono- or polysubstituted by one or more of Groups -O-, -S-, -SO-, SO2, -NR - "-, -
  • NHCONH 2 , -COOK, -OH, -NFL, HC H2, sulfonamide, sulfone, sulfoxide, or sulfonic acid), -CO-, -CR x N-O- (where Rx H, Ci -C ⁇ - Alkyl or phenyl) and / or a 3 to 10-membered, preferably 5 to 10-membered, aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from N, O and S, -SO- or -SO 2 - may be interrupted in which the hydrocarbon chain, including the side chains, if present, may be substituted by -NHCONH 2 , -COOK, -OH, -NH 2 , NH-CNH 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid.
  • L 6 is preferably a group selected from -CONH- and -NHCO-.
  • L 7 is preferably a single bond or • [CH 2) - (X 4 ) y ] w - (CH 2) z-,

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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.
EP16736012.2A 2015-06-23 2016-06-20 Conjugués anticorps-principe actif (adc) d'inhibiteurs de ksp avec des anticorps anti-b7h3 Withdrawn EP3313525A1 (fr)

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RU2751512C2 (ru) 2015-06-22 2021-07-14 Байер Фарма Акциенгезельшафт Конъюгаты антитела и лекарственного средства (adc) и конъюгаты антитела и пролекарства (apdc), содержащие ферментативно расщепляемые группы
JP6768011B2 (ja) 2015-06-23 2020-10-14 バイエル ファーマ アクチエンゲゼルシャフト キネシンスピンドルタンパク質（ｋｓｐ）阻害剤の抗ｃｄ１２３抗体との抗体薬物複合体
US11071788B2 (en) * 2015-06-23 2021-07-27 Bayer Pharma Aktiengesellschaft Antibody drug conjugates of kinesin spindel protein (KSP) inhibitors with antiB7H3-antibodies
RU2018102358A (ru) 2015-06-23 2019-07-25 Байер Фарма Акциенгезельшафт Нацеленные конъюгаты ksp ингибиторов
WO2017216028A1 (fr) 2016-06-15 2017-12-21 Bayer Pharma Aktiengesellschaft Conjugués anticorps-médicament spécifiques (adc) avec inhibiteurs de ksp et des anticorps anti-cd123
JP7030811B2 (ja) 2016-12-21 2022-03-07 バイエル・ファルマ・アクティエンゲゼルシャフト Ｋｓｐ阻害剤を有する特異的抗体－薬物コンジュゲート（ａｄｃ）
JP7066714B2 (ja) 2016-12-21 2022-05-13 バイエル・ファルマ・アクティエンゲゼルシャフト 酵素的に切断可能な基を有する抗体薬物コンジュゲート（ａｄｃ）
TW201909926A (zh) * 2017-08-04 2019-03-16 大陸商江蘇恆瑞醫藥股份有限公司 Ｂ７ｈ３抗體－藥物偶聯物及其醫藥用途
WO2020103100A1 (fr) * 2018-11-22 2020-05-28 Suzhou Kanova Biopharmaceutical Co., Ltd. Anticorps anti-b7-h3
WO2020113094A1 (fr) 2018-11-30 2020-06-04 Nuvation Bio Inc. Composés pyrrole et pyrazole et leurs procédés d'utilisation
WO2020238926A1 (fr) * 2019-05-28 2020-12-03 Single Cell Technology, Inc. Anticorps anti-b7-h3
US20230293738A1 (en) * 2020-04-24 2023-09-21 Y-Mabs Therapeutics, Inc. B7H3 Antibodies with Chelators
AU2020482800B2 (en) * 2020-12-23 2025-08-21 Genequantum Healthcare (Suzhou) Co., Ltd. Novel isomeric compounds comprising a ring-opened thiosuccinimide group, an oligopeptide fragment and a chiral moiety
CN115894689A (zh) * 2021-09-30 2023-04-04 百奥泰生物制药股份有限公司 抗b7-h3抗体及其应用
US20260055188A1 (en) * 2022-08-19 2026-02-26 Shenghe (China) Biopharmaceutical Co., Ltd. Bispecific antibody and use thereof

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2412377A1 (fr) * 2000-06-06 2001-12-13 Bristol-Myers Squibb Company Acides nucleiques et polypeptides apparentes a b7 utiles pour effectuer une immunomodulation
JP2010523478A (ja) * 2007-03-22 2010-07-15 スローン − ケタリング・インスティテュート・フォー・キャンサー・リサーチ モノクローナル抗体８ｈ９の使用
WO2012019024A2 (fr) * 2010-08-04 2012-02-09 Immunogen, Inc. Molécules se liant à her3 et leurs immunoconjugués
PE20190658A1 (es) * 2012-02-24 2019-05-08 Abbvie Stemcentrx Llc Moduladores y metodos de empleo novedosos
WO2014093640A1 (fr) * 2012-12-12 2014-06-19 Mersana Therapeutics,Inc. Conjugués hydroxy-polymère-médicament-protéine
BR112015019909A2 (pt) * 2013-02-22 2017-08-29 Abbvie Stemcentrx Llc Conjugados anticorpo-fármaco, composição farmacêutica, usos dos mesmos, e kit
US9498540B2 (en) * 2013-03-15 2016-11-22 Novartis Ag Cell proliferation inhibitors and conjugates thereof
EP2968591A1 (fr) * 2013-03-15 2016-01-20 Novartis AG Inhibiteurs de la prolifération cellulaire et leurs conjugués
AU2014312310A1 (en) * 2013-08-28 2016-04-07 Abbvie Stemcentrx Llc Novel SEZ6 modulators and methods of use
PE20160209A1 (es) * 2013-08-28 2016-05-09 Stemcentrx Inc Conjugados anti-dll3 (ligando3 tipo delta) manipulados y metodos de uso
EA032231B1 (ru) * 2013-10-11 2019-04-30 Мерсана Терапьютикс, Инк. Конъюгаты белок-полимер-лекарственное средство
PL3086814T3 (pl) * 2013-12-23 2020-12-28 Bayer Pharma Aktiengesellschaft Koniugaty środka wiążącego (ADC) z inhibitorami KSP
WO2015189143A1 (fr) * 2014-06-12 2015-12-17 Bayer Pharma Aktiengesellschaft Anticorps anti-tweakr aglycosylés et leurs utilisations
CN107635586B (zh) * 2014-12-15 2021-09-24 拜耳医药股份有限公司 Ksp抑制剂与无糖基化抗-tweakr抗体的抗体-药物缀合物(adc)
US11071788B2 (en) * 2015-06-23 2021-07-27 Bayer Pharma Aktiengesellschaft Antibody drug conjugates of kinesin spindel protein (KSP) inhibitors with antiB7H3-antibodies

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JP2018524313A (ja) 2018-08-30
CN108025085A (zh) 2018-05-11
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WO2016207103A1 (fr) 2016-12-29
AR108021A1 (es) 2018-07-11
US20180185510A1 (en) 2018-07-05

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