EP3310440A1 - Binder-wirkstoff-konjugate (adcs) und binder-prodrug-konjugate (apdcs) mit enzymatisch spaltbaren gruppen - Google Patents

Binder-wirkstoff-konjugate (adcs) und binder-prodrug-konjugate (apdcs) mit enzymatisch spaltbaren gruppen

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Publication number
EP3310440A1
EP3310440A1 EP16730833.7A EP16730833A EP3310440A1 EP 3310440 A1 EP3310440 A1 EP 3310440A1 EP 16730833 A EP16730833 A EP 16730833A EP 3310440 A1 EP3310440 A1 EP 3310440A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
cooh
seq
group
antibody
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP16730833.7A
Other languages
German (de)
English (en)
French (fr)
Inventor
Hans-Georg Lerchen
Anne-Sophie Rebstock
Yolanda Cancho Grande
Leo MARX
Beatrix Stelte-Ludwig
Carsten TERJUNG
Christoph Mahlert
Simone Greven
Anette Sommer
Sandra Berndt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Bayer Pharma AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Publication of EP3310440A1 publication Critical patent/EP3310440A1/de
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • 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
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • 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
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Definitions

  • ADCs Binder drug conjugates
  • APDCs Binder prodrug conjugates
  • the invention relates to novel binder-prodrug conjugates (APDCs) in which binders are conjugated to inactive precursor compounds of kinesin spindle protein inhibitors, and to binder-drug conjugates ADCs, active metabolites of these binder-prodrug conjugates, and binder-drug conjugates , A method for producing these APDCs or ADCs, the use of these conjugates for the treatment and / or prevention of diseases and the use of these conjugates for the preparation of medicaments for the treatment and / or prevention of diseases, in particular hyperproliferative and / or angiogenic diseases such as cancers. Such treatments may be monotherapy or in combination with other medicines or other therapeutic measures.
  • the binder is preferably an antibody according to the invention.
  • Cancers are the result of uncontrolled cell growth of various tissues. In many cases, the new cells invade existing tissues (invasive growth) or they metastasize to distant organs. Cancers occur in various organs and often have tissue-specific disease courses. Therefore, the term cancer as a generic term describes a large group of defined diseases of various organs, tissues and cell types.
  • early stage tumors may be removed by surgical and radiotherapeutic measures.
  • metastatic tumors can only be treated palliatively by chemotherapeutic agents.
  • the goal here is to achieve the optimal combination of improving the quality of life and extending the lifetime.
  • ADCs antibody drug conjugates
  • cytotoxic agent Conjugates of binder proteins with one or more drug molecules are known, in particular in the form of so-called “antibody drug conjugates” (ADCs), in which an internalizing antibody directed against a tumor-associated antigen is covalently linked via a linking unit (“left") with a
  • ADCs antibody drug conjugates
  • cytotoxic agent Conjugate is then released within the tumor cell, either the cytotoxic agent itself or another cytotoxic metabolite formed therefrom, and there can develop its action directly and selectively.
  • the damage to normal tissue could be kept within significantly narrower limits compared to conventional cancer chemotherapy [see, eg, JM Lambert, Curr. Opin. Pharmacol.
  • WO2012 / 171020 describes ADCs in which several toxophore molecules are linked to an antibody via a polymeric linker.
  • substances SB 743921, SB 715992 (Ispinesib), MK-0371, AZD8477, AZ3146 and AR Y-520 are mentioned as possible toxophores in WO2012 / 171020.
  • Kinesin spindle protein inhibitors Kinesin spindle protein (KSP, also known as Eg5, HsEg5, KNSL1, or KIF11) is a kinesin-like motor protein that is essential for the function of the bipolar mitotic spindle. Inhibition of KSP leads to mitotic arrest and apoptosis for a prolonged period of time (Tao et al., Cancer Cell 2005 Jul 8 (1), 39-59).
  • KSP inhibitors After finding the first cell-derived KSP inhibitor, monastrol, KSP inhibitors have become established as a class of new chemotherapeutic agents (Mayer et al., Science 286: 971-974, 1999) and are the subject of a number of patent applications (eg, WO2006 / 044825 WO2006 / 002236, WO2005 / 051922, WO2006 / 060737, WO03 / 060064, WO03 / 040979, and WO03 / 049527).
  • KSP inhibitors since KSP is active only in a short period of the mitotic phase, KSP inhibitors must be present in a sufficiently high concentration during this phase.
  • WO2014 / 151030 discloses ADCs with certain KSP inhibitors.
  • Legumain is a tumor-associated asparaginyl endopeptidase (S.Ishii, Methods Enzymol., 1994, 244, 604; JM Chen et al., J. Biol. Chem. 1997, 272, 8090) and has been used to process prodrugs of small cytotoxic molecules as used, inter alia, by doxorubicin and etoposide derivatives (W. Wu et al., Cancer Res. 2006, 66, 970; L. Stern et al., Bioconjugate Chem., 2009, 20, 500; KM Bajjuri et al., ChemMedChem 2011, 6, 54).
  • lysosomal enzymes are, for example, cathepsin or glycosidases such as, for example, ⁇ -glucuronidases, which have also been used for the release of the active ingredients by enzymatic cleavage of prodrugs.
  • Enzymatically cleavable groups in particular are 2-8-oligopeptide groups or glycosides.
  • Peptide cleavage sites are described in Bioconjugate Chem. 2002, 13, 855-869, and Bioorganic & Medicinal Chemistry Letters 8 (1998) 3341-3346 and Bioconjugate Chem. 1998, 9, 618-626. These include, for example, valine-alanine, valine-lysine, valine-citrulline, alanine-lysine and phenylalanine-lysine (optionally with additional amide group).
  • binder conjugates have been provided with peptide derivatives that can be released by tumor-associated enzymes such as legumain or cathepsin.
  • the tumor selectivity is thus not only determined by the choice of antibody, but additionally by the enzymatic cleavage of the peptide derivative, e.g. determined by the tumor-associated enzyme Legumain.
  • the peptide derivative may be present in the linker linking the binder to the KSP inhibitor.
  • ADCs binder-drug conjugates
  • the kinesin spindle protein inhibitors used according to the invention have an amino group which is essential for the action. By modifying this amino group with peptide derivatives, the effect on the kinesin spindle protein is blocked and thus also the unfolding of a cytotoxic effect is inhibited. However, if this peptide residue can be released by tumor-associated enzymes such as legume, the effect can be selectively restored in the tumor tissue.
  • the modification of the amino group in this case is not part of the linker.
  • the present invention relates to binder conjugates with inactive precursor molecules of kinesin spindle protein inhibitors, which are processed only in the tumor by the tumor-associated lysosomal endopeptidase legumain to the active metabolites, thus targeted to re-unfold their cytotoxic activity in the tumor.
  • the binder conjugates with KSP inhibitors, the free amino group of which is correspondingly blocked, are also referred to as APDCs according to the invention.
  • the APDCs are particularly preferred.
  • the invention provides conjugates of a binder or derivative thereof with one or more drug molecules or one or more prodrugs thereof of the following Formula I:
  • Xi N, N X 2 and X 3 is C;
  • Xi N, X 2 is C and X 3 is N;
  • X 1 is CH or CF, X 2 is C and X 3 is N; or
  • Xi is NH, X 2 is C and X 3 is C;
  • Xi CH, X 2 is N and X 3 is C;
  • R 1 is H, -L- # 1, -MOD or - (CH 2 ) 0 - 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen,
  • Y 1 and Y 2 are independently -H, -NH 2, - (CH 2 CH 2 O) 0-3 - (CH 2) 0 - 3.
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 ,
  • C 1-6 represents alkyl or aryl or benzyl optionally substituted with -NH 2 ;
  • R 2 represents -L-1, H, -MOD, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • Z is -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 , wherein Y 1 and Y 2 are independently -H, -NH 2 , or - (CH 2 ) o- 3 Z ', and Y 3
  • R 4 represents -L- # 1, -H, -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 , where Y 1 and Y 2 are independently -H, -NH 2 , or - (CH 2 ) o-3Z ', and Y 3 represents H or - (CH 2 ) o- 3 Z', wherein Z 'represents -H, -SO 3 H, -NH 2 or -COOH;
  • Y 4 is linear or branched, optionally substituted by -NHCONH2, C 1-6 alkyl or optionally substituted by -NH2 substituted aryl or benzyl and Y 5 ⁇ or -CO-CHY 6 -NH 2 , wherein Y 6 linear or branched Ci -e is alkyl;
  • R 4 is a group of the formula R 21 - (CO) ( oi) - (P 3) (o-2) -P 2 -NH-CH (CH 2 CONH 2 ) -CO- or R 21 - (CO) ( oi) - (P3) (o-2) -P2 -NH-CH (CH 2 COOH) CO-, or the cleavable by cathepsin group of formula R 21 - (CO) (oi) - (P3) (i-2) -P2 - represents, represents
  • R 21 is a Ci-10-alkyl, csio-aryl or C6-io-aralkyl, Cs-io-heteroalkyl, C 1-10 -alkyl-0-C6-io-aryl, Cs-io-heterocycloalkyl -, heteroaryl, heteroaryl-alkyl, C1-10-alkoxy, C6-io-aryloxy or C6-io-aralkoxy, Cs-io-heteroalkoxy, Ci_io-alkyl-0-C6-10 aryloxy- Represents C5-io-heterocycloalkoxy group which is mono- or polysubstituted by - - NH 2 , -NH-alkyl, -N (alkyl) 2 , -NH-CO-alkyl, -N (alkyl) -COalkyl, -SO 3 H, -SO 2 NH 2 , -
  • P2 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citrulline and His;
  • P3 an amino acid is selected from Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citrulline and His or one of the respective N-alkyl-amino acids, preferably N-methyl-Aminsoäuren is (if more than one P3 is present, P3 may therefore have different meanings); or R 2 and R 4 together (to form a pyrrolidine ring) -CH 2 -CHR 10 - or - CHR 10 -CH 2 - represent wherein R 10 is -H, -NH 2, -SO 3 H, -COOH, -SH, halogen (in particular F or Cl), C is alkyl, C 1-4 haloalkyl, C is alkoxy, hydroxyl-substituted C 1-6 alkyl, COO (C 1-4 alkyl) -OH and wherein the hydrogen
  • R 3 represents -L- # 1, -MOD, or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably -L- # 1 or a Ci-io-alkyl, C6 -io-aryl or C6-io-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-0-C6-io-aryl or C5-io-heterocycloalkyl group,
  • alkyl is preferably Ci-io alkyl
  • Z is -H, -OY 3 , -SY 3 , halogen, -NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 , where Y 1 and Y 2 independently of one another are -H, -NH 2 , or - (CH 2 ) o-3Z ', and Y 3 represents -H or - (CH 2 ) 0 - 3 Z', wherein Z 'is -H, -SO 3 H, -NH 2 or -COOH;
  • R 6 and R 7 are independently -H, cyano, (optionally fluorinated) Ci-io-alkyl, (optionally fluorinated) C 2 _io-alkenyl, (optionally fluorinated) C 2 -io-alkynyl, hydroxy, -NO 2 , -NH 2 , -COOH or halogen (especially -F, -Cl, -Br),
  • R 8 (optionally fluorinated) Ci-io-alkyl, (optionally fluorinated) C 2 _io-alkenyl, (optionally fluorinated) C 2-10 alkynyl, (optionally fluorinated) C 4 -io-cycloalkyl or (CH 2) from 0 - 2 - (2 HZ), wherein HZ 2 is a 4 to 7-membered heterocycle having up to two heteroatoms selected from N, O and S wherein each of these groups may be substituted by -OH, -CO 2 H, -NH 2 or -L- # 1;
  • R 9 is -H, -F, -CH 3 , -CF 3 , -CH 2 F or -CHF 2 ; wherein one of the substituents R 1 , R 2 , R 3 , R 4 and R 8 represents -L- # 1 or (in the case of R 8 ),
  • n 0 or 1
  • 0 is 0 or 1
  • G2 is a straight-chain and / or branched hydrocarbon group having 1 to 10 carbon atoms, which is mono- or polysubstituted by one or more of
  • R y is H, phenyl, Cj -Cj Q-alkyl, C 2 -C 10 alkenyl, or C 2 -
  • Sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted, and
  • G3 represents -H or -COOH
  • group -MOD preferably has at least one group -COOH; wherein one or more of the following conditions (i) to (iii) is satisfied: (i) -L- # l comprises a grappe of the formula - (CO) (oi) - (P 3) ( o-2) -P 2 -NH-CH (CH 2 COX) -CO-,
  • X represents -NH 2 or -COOH, preferably -NH 2
  • P2 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citralline, and His ;
  • P3 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citralline and His;
  • R 4 is the group of the formula R 2 ⁇ CO) (o) - (P 3) ( o-2) -P 2 -NH-CH (CH 2 CONH 2 ) -CO- or the cathepsin-cleavable grappe of the formula R 21 represents - (CO) (oi) - (P3) (o-2) -P2-,
  • P2 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citrulline, and His is;
  • P3 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citralline and His, or one of the respective N-alkyl amino acids, preferably N-methyl amino acids;
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR 10 - or -CHR 10 -CH 2 -, wherein the secondary hydrogen atom of the secondary amine moiety of the pyrrolidine ring is represented by R 21 -CO-P 3 ( o-2 ) -P2-NH-CH (CH 2 CONH 2 ) - CO-SIG-, where SIG is a self-immolative grappe which releases the secondary amine after cleavage of the CO-SIG bond;
  • -L- # l - is the grappe of the formula - (CO) (o-i) - (P 3) (o-2) -P 2 -NH-CH (CH 2 COX) -CO- , Particularly preferred are those groups of the formula - (CO) (o) - (P 3) ( o-2) -P 2 -NH-CH (CH 2 CONH 2 ) -CO-, that is, in the legume assay described in the experimental part fissured. Particularly preferably, one of the substituents R 1 , R 3 or R 4 represents -L- # l. When R 4 represents -L- # 1, the carbonyl group of asparagine or aspartic acid directly binds to the nitrogen atom, that in the above formula R 4 binds.
  • R 4 R 21 is - (CO) (oi) - (P 3) ( o-2) -P 2 -NH-CH (CH 2 COX) -CO- or the cathepsin-cleavable grappe of the formula R 21 - (CO) (oi) - (P3) (i-2) -P2-, or the hydrogen atom of the NH in the pyrrolidine ring is replaced by R 21 -CO-P 3 (o-2) -P 2 -NH-CH (CH 2 COX) -CO-SIG- replaced.
  • R 21 - (CO) (oi) - (P 3) ( o-2) -P 2 -NH-CH (CH 2 COX) -CO- or R 21 -CO-P 3 -P 2 N-NH-CH (CH 2 COX ) -CO-SIG- are probably cleaved in vivo by the enzyme Legumain.
  • the legume-cleavable group has the formula - (CO) (oi) - (P 3) (o-2) -P 2 -NH-CH (CH 2 CONX .) -CO- on
  • the group preferably has the formula R21- (CO) (oi) - (P3) (o-2) -P2 -NH-CH (CH 2 COX) -CO- # on, ie the group cleavable by legumain has at one end the group R 21 , at the other end (- #) it binds to the amino group corresponding to position R4 in formula IIa.
  • NH-CH (CH2COX) -CO- ie asparagine or aspartic acid
  • APDCs of the present invention may have, in addition to the legume or cathepsin-cleavable group R 1, a linker L-1 having a legume or cathepsin-cleavable group.
  • -NH-CH (CH2CONH2) -CO- in the legume-cleavable group is asparagine
  • - NH-CH (CH2COOH) -CO- in the legume-cleavable group is aspartic acid.
  • Asparagine and aspartic acid are present as L (-) - asparagine and L-aspartic acid.
  • the cleavable by Legumain group has asparagine or aspartic acid 1 to 3 other amino acids (in the case of asparagine -P2-NH-CH (CH2CONH2) - CO- - P3-P2-NH-CH (CH 2 CONH 2 ) -CO; - (P 3) (2) -P 2 -NH-CH (CH 2 CONH 2 ) -CO-), ie is a di-, tri-, or tetrapeptide or derivative thereof (dipeptide: -P 2 -NH-CH (CH 2 CONH 2) - CO-; tripeptide: -P3-P2-NH-CH (CH 2 CONH 2) -CO; tetrapeptide - (P3) -P2 2-NH- CH (CH2CONH2) -CO- (wherein the two amino acids P3 may be different).
  • P2 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citrulline and His, preferably selected from Ala, Gly, Val, Leu, He, Pro, Ser, Thr, Citrulline and Asn.
  • P2 is regularly present in the natural L configuration. Particularly preferred is L-Ala.
  • P3 is an amino acid selected from Gly, Pro, Ala, Val, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citrulline, or any of the respective ones N-alkyl-amino acids, preferably N-methyl-amino acids.
  • P3 is preferably selected from His, Pro, Ala, Val, Leu, Ile, Gly, Ser, Phe, Citrulline and Gin.
  • P3 is regularly in the natural L configuration. Particularly preferred is L-Ala. If more than one If amino acid P3 is present, these amino acids may differ within the scope of the above definition.
  • legume cleavable group -L-Ala-L-Ala-L-Asn- in the case of the APDCs R 21 -L-Ala-L-Ala-L-Asn-#).
  • R 21 preferably represents -H, a C 1-5 -alkyl, C 3-10 -aralkyl, C 1-5 -alkoxy, C 1-10 -aryloxy, C 1-10 -heteroalkyl-, C 1-10 -heterocycloalkyl- , Heteroaryl, heteroaryl-alkyl, C 5-10 heteroalkoxy, or a C 1-10 heterocycloalkoxy group, which may be substituted in each case by --COOH, COOalkyl, COONH 2, NH 2 or N (alkyl) 2 , or a group -O x - (CH 2 CH 2 O) y -R 22 , (where x is 0 or 1 and v is a number from 1 to 20, and R 22 is - H, -alkyl -CH 2 -COOH, - CH2-CH2-COOH, or -CH2-CH2-NH2).
  • Alkyl denotes here an alkyl group having up to 20 carbon
  • the cathepsin-cleavable group has the formula - (CO) oi ) - (P3) ( i-2 ) -P2-.
  • the group has the formula R 21 - (CO) (oi ) - (P 3) ( i-2 ) -P 2 - #, ie the cathepsin-cleavable group has at one end the group R 21 , on the other end (- #) binds to the amino group corresponding to position R4 in formula IIa.
  • R21, P2 and P3 have the same meaning as in legumain-cleavable group.
  • cathepsin-cleavable groups are those in which P2 is selected from alanine, lysine and citrulline, and P3 is selected from valine, alanine and phenylalanine, especially those of the formula R 21 - (CO) (oi ) -P 3-P2- ,
  • FIG. 1 Alignment of the TWEAKR cysteine-rich domain (amino acids 34 to 68) of different species. (The numbers show the amino acid position in full-length constructs including the signal sequences; SEQ ID NO: 169).
  • FIG. 2 A - Schematic diagram of the structure of TWEAKR (SEQ ID NO: 169).
  • Diagram shows the extracellular domain (amino acids 28-80) (SEQ ID NO: 168) including the cysteine-rich domain (36-67), the transmembrane domain - TM (81-101), and the intracellular domain (102-129).
  • TPP-2202 the complete ectodomain (28-80), fused to the Fc domain of hlgGl.
  • TPP 2203 extracellular domain with N- and C-terminal truncation (34-68) fused to the Fc domain of hlgGl.
  • Disulfide bridges Cys36-Cys49, Cys52-Cys67 and Cys55-Cys64 are indicated by black bars.
  • TPP-2203 receives two amino acids and one more amino acid at the C-terminal compared to the pure cysteine-rich domain to ensure proper folding.
  • P4A8 (TPP-1324) binds only to the full-length extracellular domain (TPP-2202).
  • FIG. 4 Representation of successively connected enzymatic steps for
  • the invention provides conjugates of a binder or derivative thereof with one or more drug molecules or prodrugs thereof, wherein the drug molecule is a kinesin spindle protein inhibitor (KSP inhibitor).
  • KSP inhibitor kinesin spindle protein inhibitor
  • KSP-L in formula I has the following formula (IIa):
  • Xi N, N X 2 and X 3 is C;
  • Xi N, X 2 is C and X 3 is N;
  • X 1 is CH or CF, X 2 is C and X 3 is N; or
  • Xi is NH, X 2 is C and X 3 is C;
  • Xi CH, X 2 is N and X 3 is C;
  • R 1 is -H, -L- # 1, -MOD or - (CH 2 ) 0 - 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen,
  • Y 1 and Y 2 are independently -H, -NH 2, - (CH 2 CH 2 O) 0-3 - (CH 2) 0 - 3.
  • Y 4 is linear or branched, optionally substituted by-NHCONH 2 , Ci-6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl;
  • R 2 represents -L-1, -H, -MOD, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • Z is -H, halogen, -OY 3 , -SY 3 , -NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 , where Y 1 and Y 2 are independently -H, -NH 2 , or - (CH 2 ) o- 3 Z ', and Y 3 represents -H or - (CH 2 ) 0 - 3 Z', wherein Z 'is -H, -SO 3 H, -NH 2 or -COOH; wherein Y is linear or branched, optionally substituted with-NHCONH2, Ci_6 alkyl or optionally substituted with -NH2 substituted aryl or benzyl and Y 5 ⁇ or -CO-CHY 6 -NH 2 , wherein Y 6 represents linear or branched C1-6 alkyl ;
  • R 4 represents -L- # 1, H, -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 , wherein Y 1 and Y 2 are independently -H, -NH 2 , or - (CH 2 ) o-3Z ', and Y 3
  • C 1-6 is alkyl or aryl or benzyl optionally substituted with -NH 2 and
  • Y 5 represents ⁇ or -CO-CHY 6 -NH 2 , wherein Y 6 represents linear or branched C 1 -e alkyl;
  • R 4 is a group of the formula R 21 - (CO) ( oi) - (P 3) (o-2) -P 2 -NH-CH (CH 2 CONH 2 ) -CO- or R 21 - (CO) ( oi) - (P3) (o-2) -P2 -NH-CH (CH 2 COOH) CO-, or the cleavable by cathepsin group of formula R 21 - (CO) (oi) - (P3) (i-2) -P2 - represents
  • R 21 is a Ci-10-alkyl, csio-aryl or C6-io-aralkyl, Cs-io-heteroalkyl, C 1-10 -alkyl-0-C6-io-aryl, Cs-io-heterocycloalkyl -, heteroaryl, heteroaryl-alkyl, C1-10-alkoxy, C6-io-aryloxy or C6-io-aralkoxy, Cs-io-heteroalkoxy, Ci_io-alkyl-0-C6-10 aryloxy- Represents C5-io-heterocycloalkoxy group which is mono- or polysubstituted with -NH 2 , -NH-alkyl, -N (alkyl) 2 , NH-CO-alkyl, N (alkyl) -COalkyl, -SO 3 H, -SO 2 NH 2 , - S0 2 -N
  • P2 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citrulline and His;
  • P3 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citrulline and His or one the respective N-alkyl-amino acids, preferably N-methyl-amino acids; or R 2 and R 4 together (to form a pyrrolidine ring) -CH 2 -CHR 10 - or - CHR 10 -CH 2 - represent wherein R 10 is H, NH 2, S0 3 H, COOH, SH, halo (especially F or Cl), C is alkyl, C is haloalkyl, C is alkoxy, hydroxyl-substituted C is alkyl, COO (C-C-alkyl), OH or R 21 is -CO-P 3 -P2 -NH-CH (CH 2 CONH 2 ) -CO-SIG- represents, where SIG represents
  • R 3 represents -L- # 1, -MOD, or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably -L- # 1 or a Ci-io-alkyl, C6 -io-aryl or C6-io-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-0-C6-io-aryl or C5-io-heterocycloalkyl group,
  • alkyl is preferably coco-alkyl
  • 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 ) o-3Z ', and Y 3 represents H or - (CH 2 ) 0 - 3 Z', wherein Z 'represents -H, -SO 3 H, -NH 2 or -COOH;
  • R 6 and R 7 are independently -H, cyano, (optionally fluorinated) Ci-io-alkyl, (optionally fluorinated) C 2 _io-alkenyl, (optionally fluorinated) C 2 .io-alkynyl, hydroxy, -NO 2 , -NH 2 , -COOH or halogen (especially -F, -Cl, -Br),
  • R 8 (optionally fluorinated) Ci-io-alkyl, (optionally fluorinated) C 2 _io-alkenyl, (optionally fluorinated) C 2-10 alkynyl, (optionally fluorinated) C 4 -io-cycloalkyl or (CH 2) from 0 - 2 - (2 HZ), wherein HZ 2 is a 4 to 7-membered heterocycle having up to two heteroatoms selected from N, O and S wherein each of these groups may be substituted by -OH, -CO 2 H, -NH 2 or -L- # 1;
  • R 9 is -H, -F, -CH 3 , -CF 3 , -CH 2 F or -CHF 2 ; wherein one of the substituents R 1 , R 2 , R 3 , R 4 and R 8 represents -L- # 1 or (in the case of R 8 ),
  • G1 is - or ⁇ / (where if G is -NHCO- or , R lu is not -NH 2);
  • n 0 or 1
  • 0 is 0 or 1
  • G2 is a straight-chain and / or branched hydrocarbon group having 1 to 10 carbon atoms, which is mono- or polysubstituted by one or more of
  • Alkenyl, or C 2 -C 10 alkynyl, each with NHC ( 0) NH 2 , -COOH, -OH,
  • G 3 represents -H or -COOH
  • group -MOD preferably has at least one group -COOH; wherein one or more of the following conditions (i) to (iii) is satisfied: (i) -L- # l comprises a group of the formula - (CO) (oi) - (P 3) ( o-2) -P 2 -NH-CH (CH 2 COX) - CO-,
  • X represents -NH 2 or -COOH, preferably -NH 2;
  • P2 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, He, Met, Phe,
  • P3 an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, He, Met, Phe,
  • R 4 is the group of formula R 21 - (CO) (oi) - (P 3) (o-2) -P 2 -NH-CH (CH 2 CONH 2) -CO- or the cathepsin-cleavable group of formula R 21 represents - (CO) (oi) - (P3) (i-2) - P2-,
  • P2 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citrulline, and His
  • P3 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citrulline and His;
  • R 2 and R 4 together represent (to form a pyrrolidine ring) -CH 2 -CHR- or -CHR 10 -CH 2 - wherein the secondary hydrogen atom of the secondary amine group of the pyrrolidine ring is represented by R 21 -CO-P 3-P2 -NH - CH (CH2CONH2) -CO-SIG-, where SIG is a self-immolative group that releases the secondary amine after cleavage of the CO-SIG bond;
  • substituted means that one or more hydrogens on the designated atom or group are replaced by a selection from the group indicated, provided that the normal valence of the designated atom has not been exceeded under the present circumstances Combinations of substituents and / or variables are permitted.
  • substituted groups may be substituted by as many optional substituents as may be substituted by replacing a hydrogen atom with a non-hydrogen substituent on any one of them accommodate available carbon or nitrogen or sulfur atom.
  • the number of optional substituents may be 1, 2, 3, 4 or 5, especially 1, 2 or 3.
  • the term "one or more times", for example, in the definition of the substituents of the compounds of the general formulas of the present invention, means "1, 2, 3, 4 or 5, preferably 1, 2, 3 or 4, more preferably 1, 2 or 3, most preferably 1 or 2 ".
  • radicals are substituted in the compounds according to the invention, the radicals can, unless stated otherwise, be monosubstituted or polysubstituted.
  • the meanings of all residues that occur multiple times are independent of each other. Substitution by one, two or three identical or different substituents is preferred. Substitution by a substituent is particularly preferred.
  • Alkyl is a linear or branched, saturated, monovalent hydrocarbon radical having 1 to 10 carbon atoms (Ci-CIO alkyl), usually 1 to 6 (Ci-C 6 - alkyl), preferably 1 to 4 (Ci- C i- Alkyl), and particularly preferably 1 to 3 carbon atoms (C 1 -C 3 -alkyl).
  • Particularly preferred is a methyl, ethyl, propyl, isopropyl and tert-butyl radical.
  • Heteroalkyl represents a straight-chain and / or branched hydrocarbon chain having 1 to 10
  • Carbon atoms which are mono- or polysubstituted by one or more of the groups -O-, -S-,
  • Sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted.
  • R x is -H, C 1 -C 3 -alkyl or phenyl.
  • Alkenyl is a straight-chain or branched monovalent hydrocarbon chain having one or two double bonds and 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (C 2 -C 10 -alkenyl), in particular 2 or 3 carbon atoms (C 2 - C3 alkenyl), it being understood that when the alkenyl group contains more than one double bond, the double bonds may be isolated from each other or conjugated with each other.
  • the group is vinyl or allyl.
  • alkynyl represents a straight-chain or branched monovalent hydrocarbon chain having one triple bond and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (C 2 -C 10 -alkynyl), in particular 2 or 3 carbon atoms (C 2 -C 3 ) alkynyl).
  • the C 2 -C 6 alkynyl group is, for example, an ethynyl, prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl , But-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl , Hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1 Methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl,
  • alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
  • Cycloalkyl (C3 2 cycloalkyl-Ci) a saturated monovalent monocyclic or bicyclic hydrocarbon radical having 3-12 carbon atoms.
  • a monocyclic hydrocarbon radical is a monovalent
  • Hydrocarbon radical with usually 3 to 10 (C3-Cio-cycloalkyl), preferably 3 to 8
  • a monocyclic hydrocarbon radical mention may be made:
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl and
  • Heterocycloalkyl is a non-aromatic mono- or bicyclic ring system having one, two, three or four heteroatoms, which may be the same or different. As heteroatoms nitrogen atoms, oxygen atoms or sulfur atoms can occur.
  • a monocyclic ring system according to the present invention may have 3 to 8, preferably 4 to 7, 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:
  • Azepanyl, oxepanyl, 1,3-diazepanyl, 1,4-diazepanyl is Azepanyl, oxepanyl, 1,3-diazepanyl, 1,4-diazepanyl.
  • heterocycloalkyl having 8 ring atoms examples and preferred for a heterocycloalkyl having 8 ring atoms are:
  • Oxocanyl, azocanyl
  • monocyclic heterocycloalkyl 4 to 7-membered, saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S are preferred.
  • a bicyclic ring system having one, two, three or four heteroatoms, which may be the same or different, may according to the present invention have 6 to 12, preferably 6 to 10 Have ring atoms, wherein one, two, three or four carbon atoms can be exchanged for identical or different heteroatoms from the series O, N and S.
  • Examples include: azabicyclo [3.3.0] octyl, azabicyclo [4.3.0] nonyl,
  • Aryl is a monovalent, mono- or bicyclic, aromatic carbon ring system consisting of carbon atoms. Examples are naphthyl and phenyl; preferred is phenyl or a phenyl radical.
  • C6-io-Aralkyl- stands in the context of the invention for a monocyclic aromatic aryl, exemplified phenyl, to which a Ci-C i-alkyl group is attached.
  • An exemplary C6-io-aralkyl group is benzyl.
  • Heteroaryl means a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a 5- to 14-membered
  • Heteroaryl “group”) in particular 5, 6, 9 or 10 ring atoms, to understand that contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the group N, O and S and via a ring carbon atom or optionally (if the valence allowed) via a ring nitrogen atom is bound.
  • the heteroaryl group may be a 5-membered heteroaryl group such as thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group such as carbazolyl, acridinyl or phenazinyl; or a 9-membered one Heteroaryl group such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • the bond valency may be at any aromatic carbon atom or at a nitrogen atom.
  • a monocyclic heteroaryl group according to the present invention has 5 or 6 ring atoms. Preference is given to those heteroaryl radicals having one or two heteroatoms. Particularly preferred are one or two nitrogen atoms.
  • heteroaryl radicals having 5 ring atoms include the rings:
  • Heteroaryl radicals having 6 ring atoms include, for example, the rings:
  • a bicyclic heteroaryl group according to the present invention has 9 or 10 ring atoms.
  • heteroaryl radicals having 9 ring atoms include the rings:
  • Heteroaryl radicals with 10 ring atoms include, for example, the rings:
  • Sulfone, sulfoxide, or sulfonic acid may be substituted
  • Sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted.
  • R x 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 alkyl, alkenyl and alkynyl may be substituted one or more times by fluorine.
  • Xi N, X 2 is C and X 3 is N;
  • X 1 is CH or CF, X 2 is C and X 3 is N; or
  • Xi is NH, X 2 is C and X 3 is C;
  • Xi CH, X 2 is N and X 3 is C;
  • R 1 is -H-MOD or - (CH 2 ) 0 - 3 Z, where Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-
  • NY'Y 2 or represents -CO-OY 3 ,
  • Y 1 and Y 2 are independently -H, -NH 2, - (CH 2 CH 2 O) 0-3 - (CH 2) 0 - 3.
  • Y 4 is linear or branched, optionally substituted by-NHCONH 2 , Ci-6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl;
  • R 2 represents -H, -MOD, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • Z is -H, halogen, -OY 3 , -SY 3 , NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 , wherein Y 1 and Y 2 are independently -H, -NH 2 , or - (CH 2 ) o- 3 Z ', and Y 3
  • C 1-6 is alkyl or aryl or benzyl optionally substituted with -NH 2 and
  • Y 5 represents H or -CO-CHY 6 -NH 2 , wherein Y 6 represents linear or branched C 1-6 alkyl;
  • R 4 is a group of the formula R 21 - (CO) ( oi) - (P 3) (o- 2 ) -P 2 -NH-CH (CH 2 CONH 2 ) -CO- or R 21 - (CO) ( oi) - ( P3) (o- 2 ) -P2-NH-CH (CH 2 COOH) -CO- or the cathepsin-cleavable group of the formula R 21 - (CO) ( 0 -i ) - (P 3) ( i- 2) - P2- represents,,
  • R 21 is a Ci-io-alkyl, csio-aryl or C6-io-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-0-C6-io-aryl, Cs-io-heterocycloalkyl -, heteroaryl, heteroaryl-alkyl, Ci-io-alkoxy, C6-io-aryloxy or C6-io-aralkoxy, Cs-io-heteroalkoxy, Ci_io-alkyl-0-C6-lo-aryloxy Represents Cs-io-heterocycloalkoxy group which is mono- or polysubstituted with - NH 2 , -NH-alkyl, -N (alkyl) 2 , NH-CO-alkyl, N (alkyl) -COalkyl, -SO 3 H, - S0 2 NH 2 , -
  • P2 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citrulline and His;
  • R 3 is -MOD, or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, a Ci-io-alkyl, C6-io-aryl or Ce-io- aralkyl, C 1-10 -heteroalkyl, C 1-10 -alkyl-0-C 6 -10-aryl or C 1-10 -heterocycloalkyl groups which are substituted by 1 -3 -OH groups, 1 -3 halogen atoms, 1 -3 halogenated alkyl groups ( each having 1 -3 halogen atoms), 1 -3 O-alkyl groups, 1 -3 -SH groups, 1 -3 -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
  • alkyl is preferably C1-10 alkyl
  • Z is -H, -OY 3 , -SY 3 , halogen, -NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 , where Y 1 and Y 2 independently of one another are -H, -NH 2 , or - (CH 2 ) o-3Z ', and Y 3 represents -H or - (CH 2 ) 0 - 3 Z', wherein Z 'is -H, -SO 3 H, -NH 2 or -COOH;
  • R 6 and R 7 are independently -H, cyano, (optionally fluorinated) Ci-io-alkyl, (optionally fluorinated) C 2 _io-alkenyl, (optionally fluorinated) C 2 -io-alkynyl, hydroxy, -NO 2 , -NH 2 , -COOH or halogen (especially -F, -Cl, -Br), R 8 (optionally fluorinated) Ci-io-alkyl, (optionally fluorinated) C 2 -io-alkenyl, (optionally fluorinated) C 2 - 1 0 alkynyl, (optionally fluorinated) C 4 -io-cycloalkyl or - (CH 2 ) o - 2 - (HZ 2 ) wherein HZ 2 is a 4 to 7 membered heterocycle having up to two heteroatoms selected from N, O and S, each of which groups being substituted with -
  • R 9 is -H, -F, -CH 3 , -CF 3 , -CH 2 F or -CHF 2 ; wherein -MOD - (NR 10 ) n - (GI) o -G2-G3, wherein
  • R 10 is -H or C 1 -C 3 -alkyl
  • n 0 or 1
  • 0 is 0 or 1
  • group -MOD preferably has at least one group -COOH; and their salts, solvates and salts of the solvates.
  • KSP inhibitor (or KSP-L) according to formula (IIa) is conjugated with a binder
  • one of the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 8 or R 10 thus represents -L - # l, where L is the linker and # 1 is the bond to the binder or derivative thereof. That is, in the case of the conjugates, one of the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 10 represents -L- # 1, where -L- # 1 represents the binder such as an antibody represents. It is particularly preferred if one of the substituents R 1 , R 3 or R 4 represents -L- # l.
  • the binder is preferably a human, humanized or chimeric monoclonal antibody or an antigen-binding fragment thereof, in particular an anti-TWEAKR antibody or an antigen-binding fragment thereof or an anti-EGFR antibody or an antigen-binding fragment thereof or an anti-HER2 antibody.
  • an anti-TWEAKR antibody which specifically binds to amino acid D at position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the anti-TWEAKR antibodies TPP-2090 and TPP-2658 or the anti EGFR antibody cetuximab or nimotuzumab or the HER-2 antibody trastuzumab
  • 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 the binder or derivative thereof.
  • Compounds with -L- # 3 are reactive compounds that react with the binder or derivative thereof.
  • # 3 is preferably a group that reacts with an amino or thiol group to form a covalent bond, preferably with the cysteine residue in a protein.
  • the cysteine residue in a protein may be present in the protein, introduced by biochemical methods, or preferably generated by prior reduction of disulfides of the binder.
  • the carbon atom to which R 1 binds is a stereocenter which may be in the L and / or D configuration, preferably in the L configuration.
  • R 2 is not H
  • the carbon atom to which R 2 binds is a stereocenter which may be in the L and / or D configuration.
  • X 1 is CH or CF, X 2 is C and X 3 is N; Xi is NH, X 2 is C and X 3 is C; or
  • Xi CH, X 2 is N and X 3 is C;
  • X 1 represents N, X 2 N and X 3 represents C; or Xi CH, X 2 and X 3 C N represents.
  • Xi is CH, X 2 C and X 3 N are preferred.
  • CO carbonyl
  • R 1 is preferably -L- # l, -MOD, -H, -COOH, -CONHNH 2 , - (CH 2 ) i_ 3 NH 2 , -CONZ "(CH 2 ) i_ 3 NH 2 and -CONZ" CH 2 COOH, wherein Z represents "-H or -NH 2.
  • R 4 represents -L- # 1
  • R 1 is preferably -MOD (especially when R 3 is not -MOD).
  • R 2 is preferably -H.
  • R 4 -H, -L- # 1 or the legume-cleavable group of the formula R 21 is - (CO) oi) - (P 3 ) o - 2 ) - P2 -NH-CH (CH 2 CONH 2 ) -CO - prefers.
  • -L- # 1 has the group of the formula - (CO) (oi) - (P 3) ( o- 2 ) -P 2 -NH-CH (CH 2 COX) -CO * -, wherein the carbonyl group of (L-) asparagine or (L-) aspartic acid (denoted by *) binds directly to the nitrogen atom which binds to R 4 in the above formula.
  • R 4 represents -L- # 1
  • R 1 or R 3 is preferably -MOD.
  • R 4 represents -L- # 1
  • R 3 is preferably - MOD (especially when R 1 is not -MOD).
  • R 5 is preferably -H or -F.
  • R 6 and R 7 are independently of one another preferably -H, (optionally fluorinated) Ci-3-alkyl, (optionally fluorinated) C 2 _4-alkenyl, (optionally fluorinated) C 2 -4-alkynyl, hydroxy or halogen ,
  • R 8 is preferably a branched Ci-5-alkyl group, in particular a group of the formula - C (CH 3) 2 - (CH 2 ) o- 2- R y , wherein R y is -H, -OH, -C0 2 H or -NH 2 . Particularly preferred is a group of the formula -C (CH 3 ) 2 - (CH 2 ) -R y , wherein R y is -H.
  • R 9 is preferably -H or -F.
  • Preferred as -MOD is HOOC- (CHX) x -AM-CH 2 -CH 2 -NH-CO-, where x is a number from 2 to 6, X is -H, -NH 2 or -COOH, and AM - CO-NH- or -NH-CO-, (particularly preferred are HOOC-CH 2 -CH 2 -CH (COOH) -NH-CO-CH 2 -CH 2 -NH-CO-, HOOC-CH (NH 2 ) - CH 2 -CH 2 -CO-NH-CH 2 -CH 2 -NH-CO-, HOOC-CH (NH 2 ) - (CH 2 ) 4 -NH-CO-CH 2 -CH 2 -NH-CO-) ,
  • Xi is NH, X 2 is C and X 3 is C;
  • Xi CH, X 2 is N and X 3 is C;
  • R 1 is -H, -COOH, -CONHNH 2 , - (CH 2 ) i_ 3 NH 2 , -CONZ "(CH 2 ) i_ 3 NH 2 and -CONZ" CH 2 COOH where Z "is -H or -NH 2 ;
  • R 2 represents -H
  • R 4 is the leguminin-cleavable group of the formula R 21 - (CO) oi) - (P 3) (o- 2 ) -P 2 -NH-CH (CH 2 CONH 2 ) -CO-;
  • R 3 is a phenyl group which may be mono- or polysubstituted by halogen (in particular -F) or optionally fluorinated CT .3 alkyl, 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-NH-Y 4 , S (O) n -Y 4 (where n is 0, 1 or 2), -SO 2 -NH-Y 4 , NH-Y 4 , or N (Y 4 ) 2 , where Y 4 is H, phenyl (optionally one or more times with halogen (in particular F) or optionally fluorinated C 1-3 alkyl), or alkyl (where the alkyl group may be substituted by -OH, -COOH, and / or -NHCO-C 1-3
  • R 3 is -OH, -O-alkyl, -SH, -S-alkyl, -O-CO-alkyl, -O-CO-NH-alkyl, -NH-CO-alkyl, -NH-CO- NH-alkyl, -S (O) n- alkyl, -SO 2 -NH-alkyl, -NH-alkyl, -N (alkyl) 2 , or -NH2 may be substituted, n is 0, 1 or 2, (wherein alkyl is preferably C1-3 alkyl)
  • R 5 is -H or -F
  • R 6 and R 7 are independently -H, (optionally fluorinated) C 1-3 alkyl, (optionally fluorinated) C 2 -4 alkenyl, (optionally fluorinated) C 2 -4 alkynyl, hydroxy or halogen ;
  • R 8 is a branched C 1-5 alkyl group
  • R 9 is -H or -F.
  • X 1 is CH or CF, X 2 is C and X 3 is N;
  • Xi is NH, X 2 is C and X 3 is C;
  • Xi CH, X 2 is N and X 3 is C;
  • A is CO (carbonyl);
  • R 2 represents -H
  • R 3 - (CH 2 ) OH, -CH (CH 3 ) OH, -CH 2 SCH 2 CH (COOH) NHCOCH 3 , -CH (CH 3 ) OCH 3 , a phenyl group containing 1-3 halogen atoms, 1- 3 amino groups or 1-3 alkyl groups (which may optionally be halogenated), or HOOC- (CHX) x -AM-CH 2 -CH 2 -NH-CO-, where x is a number from 2 to 6, X is H, NH 2 or COOH, and AM is -CO-NH- or -NH-CO-, (especially preferred are HOOC-CH2-CH 2 -CH (COOH) -NH-CO-CH 2 CH 2 - NH-CO-; HOOC-CH (NH2) -CH2-CH2-CO -NH-CH 2 -CH 2 -NH-CO-, HOOC-CH (NH 2 ) - (CH 2 ) 4 -NH-
  • R 5 is -H or -F
  • R 8 is a branched C 1-5 alkyl group
  • R 9 is -H or -F.
  • R 2 represents -H
  • R 4 is the legume-cleavable group of the formula R 21 - (CO) (oi ) - (P 3) (o- 2) -P 2 -NH-CH (CH 2 CONH 2 ) -CO-
  • R 5 represents -H
  • R 6 and R 7 independently of one another are -H, C 1-3 -alkyl or halogen, in particular that R 6 and R 7 are -F;
  • R 8 is C 1-4 -alkyl (preferably tert-butyl).
  • R 9 represents -H
  • one of the substituents R 1 and R 3 represents -L- # l.
  • R 1 -L- # 1 COOH HOOC-CH 2 -CH 2 -CH (COOH) -NH-CO-CH 2 -CH 2 -NH-CO-; HOOC-CH (NH 2 ) -CH 2 -CH 2 -CO-NH-CH 2 -CH 2 -NH-CO-; HOOC-CH (NH 2 ) - (CH 2 ) 4 -NH-CO-CH 2 -CH 2 -NH-CO- or H,
  • R 2 represents -H
  • R 4 represents -H or the leguminine-cleavable group of the formula R 21 - (CO) oi) - (P 3) o - 2 ) -P 2 --NH - CH (CH 2 CONH 2 ) - CO -
  • R 5 represents -H
  • R 6 and R 7 independently of one another are -H, C 1-3 -alkyl or halogen, in particular that R 6 and R 7 are -F;
  • R 8 is C 1-4 -alkyl (preferably tert-butyl).
  • R 9 represents -H
  • one of the substituents R 1 and R 3 represents -L- # l.
  • Xi, X 2 , X 3 have the same meaning as in formula (IIa) (preferably with Xi CH, X 2 C and X 3 N), R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 have the same meaning as in formula (IIa)
  • B represents a single bond, -O-CH 2 - or -CH 2 -O-
  • n Represents 1, or 2.
  • Xi, X2, X3 have the same meaning as in formula (IIIa) or (III) (preferably with Xi CH, X 2 C and X 3 N)
  • R 1 represents - (CH 2 ) o - 3 Z, wherein Z represents -CO-NY'Y 2 , wherein Y 2 - (CH 2 CH 2 O) 0 - 3 - (CH 2 ) 0 3 Z 'and Y 1 represents -H, -NH 2, or - (CH 2 CH 2 O) 0 - 3 - (CH 2 ) 0 3 Z ';
  • Y 1 represents -H
  • Y 2 represents - (CH 2 CH 2 O) 3 -CH 2 CH 2 Z 'and Z represents -COOH;
  • Y 1 represents -H
  • Y 2 represents -CH 2 CH 2 Z 'and Z' - (CONHCHY 4 ) 2 COOH;
  • Y 1 is -H
  • Y 2 is -CH 2 CH 2 Z ', Z' - (CONHCHY 4 ) 2 COOH and one Y is 4- propyl and the other is - (CH 2 ) 3 -NHCONH 2 ;
  • Y 1 is -H
  • Y 2 is -CH 2 CH 2 Z ', Z' - (CONHCHY 4 ) 2 COOH and one Y 4 is -CH 3 and the other is - (CH 2 ) 3 -NHCONH 2 ;
  • Y 4 represents linear or branched, optionally substituted by -NHCONH 2 , Ci_6 alkyl;
  • Y 4 is selected from z-propyl or -CH 3 .
  • Y 1 is -H
  • Y 2 is -CH 2 CH 2 Z '
  • Z' is -CONHCHY 4 COOH
  • Y 4 is optionally aryl or benzyl substituted with -NH 2 ;
  • Y 4 represents aminobenzyl
  • R 2 is - (CH 2 ) o- 3 Z and Z is -SY 3 ;
  • R 4 is -CO-CHY 4 -NHY 5 and Y 5 is -H;
  • R 4 is -CO-CHY 4 -NHY 5 and Y 5 is -CO-CHY 6 -NH 2 ;
  • Y 4 represents linear or branched, optionally substituted with -NHCONH 2 Ci_6 alkyl. Furthermore, it is preferred that R 1 , R 2 or R 3 in formula (IIa) is -MOD, especially when R 4 is -L- # 1 (in particular when -L is a cleavable linker which is attached directly to -NR 4 or -N- L- # 1 splits, so that R 4 or L is replaced by H).
  • R 3 represents -MOD and R 1 or R 4 represents -L- # 1 and -L-BINDER, respectively, where -MOD represents - (NR 10 ) n - (G) o -G 2 -G 3, where R 10 - H or Ci-C 3 -alkyl;
  • G1 is - or ⁇ / (where if G is -NHCO- or , R lu is not -NH 2);
  • 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
  • Sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted
  • G3 represents -H or -COOH
  • group -MOD preferably has at least one group -COOH.
  • the group -MOD has a (preferably terminal) -COOH group, for example in a betaine group.
  • the group -MOD has the formula -CH 2 -S x - (CH 2) o-4 -CHY 5 -COOH, wherein x is 0 or 1, and Y 5 represents -H or -NHY 6 , wherein Y 6 is -H or - COCH3 represents.
  • preference is given (alone or in combination) if in formula (IIa), (IIb), (IIc), (IId), or (IIIe):
  • R 1 represents - (CH 2 ) o - 3 Z, wherein Z represents -CO-NY'Y 2 , wherein Y 2 - (CH 2 CH 2 O) 0 - 3 - (CH 2 ) 0 3 Z 'and Y 1 represents -H, -NH 2, or - (CH 2 CH 2 O) 0 - 3 - (CH 2 ) 0 3 Z ';
  • Y 1 represents -H
  • Y 2 represents - (CH 2 CH 2 O) 3 -CH 2 CH 2 Z 'and Z represents -COOH;
  • Y 1 represents -H
  • Y 2 represents -CH 2 CH 2 Z 'and Z' - (CONHCHY 4 ) 2 COOH;
  • Y 1 represents -H
  • Y 2 represents -CH 2 CH 2 Z ', Z' - (CONHCHY 4 ) 2 COOH and represents a representative of Y 4 z ' propyl and the other - (CH 2 ) 3 -NHCONH 2 represents;
  • Y 1 represents -H
  • Y 2 represents -CH 2 CH 2 Z ', Z' - (CONHCHY 4 ) 2 COOH and represents one representative of Y 4 -CH 3 and the other represents - (CH 2 ) 3 -NHCONH 2 ;
  • Y 4 represents linear or branched, optionally substituted by -NHCONH 2 , Ci_6 alkyl;
  • Y 4 is selected from z ' -propyl or -CH 3 .
  • Y 1 is -H
  • Y 2 is -CH 2 CH 2 Z '
  • Z' is -CONHCHY 4 COOH
  • Y 4 is optionally aryl or benzyl substituted with -NH 2 ;
  • Y 4 represents an aminobenzyl
  • R 2 is - (CH 2 ) o- 3 Z and Z is -SY 3 ;
  • R 4 is -CO-CHY 4 -NHY 5 and Y 5 is -H;
  • R 4 is -CO-CHY 4 -NHY 5 and Y 5 is -CO-CHY 6 -NH 2 ;
  • Y 4 represents linear or branched optionally substituted with -NHCONH 2 Ci_6 alkyl.
  • Xi N, N X 2 and X 3 is C;
  • Xi N, X 2 is C and X 3 is N;
  • X 1 is CH or CF, X 2 is C and X 3 is N; or
  • Xi is NH, X 2 is C and X 3 is C;
  • Xi is CH or CF, X 2 is N and X 3 is C;
  • R 1 is -H, -L- # 1, -MOD or - (CH 2 ) 0 - 3 Z, wherein Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY'Y 2 , or is -CO-OY 3 , wherein Y 1 and Y 2 are independently -H, -NH 2 , - (CH 2 CH 2 O) o-3- (CH 2 ) o-3Z '(eg - (CH 2 ) 0 - 3 Z'), or Z is -CH (CH 2 W) 'represent, and Y 3 is H or - (CH 2) 0 - 3.
  • Z' represents wherein Z '- H, -NH 2, -SO 3 H, -COOH, -NH-CO-CH 2 represents -CH 2 -CH (NH 2 ) COOH or - (CO-NH-CHY 4 ) i_ 3 COOH; where W represents -H or -OH,
  • Y 4 is linear or branched, optionally substituted with -NHCONH 2 , C 1-6 alkyl or optionally substituted with -NH 2 substituted aryl or benzyl;
  • R 2 represents -H, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • Z is -H, halogen, -OY 3 , -SY 3 , -NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 , where Y 1 and Y 2 are independently -H, -NH 2 , or - (CH 2 ) o-3Z ', and Y 3 represents -H or - (CH 2 ) 0 - 3 Z', wherein Z 'is -H, -SO 3 H, -NH 2 or -COOH;
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 ,
  • C 1-6 is alkyl or aryl or benzyl optionally substituted with -NH 2 and Y 5 "
  • R 4 is -H or the leguminable group
  • R 21 is - (CO) oi) - (P 3) o - 2 ) -P 2 -NH-CH (CH 2 CONH 2 ) -CO-;
  • R 3 represents -L- # 1, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably a C 1-10 -alkyl-, C 6 -iodo-aryl- or C6-io-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-0-C6-io-aryl or C5-10-heterocycloalkyl group containing 1-3 -OH groups, 1-3 Halogen atoms, 1-3 halogenated alkyl groups (each having 1-3 halogen atoms), 1-3 O-alkyl groups, 1-3 -SH groups, 1-3 -S-alkyl groups, 1-3 -O-CO-alkyl Groups, 1-3 -O-CO-NH-alkyl groups, 1-3 -NH-CO-alkyl groups, 1-3 -NH-CO-alkyl
  • Y 1 and Y 2 are independently -H, -NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is -H or - (CH 2 V 3 Z', wherein Z 'is -H, -SO 3 H, -NH Represents 2 or -COOH;
  • R 6 and R 7 are independently -H, cyano, (optionally fluorinated) Ci 1 0-alkyl, (gg fluorinated) C2-io-alkenyl, (optionally fluorinated) C2-io alkynyl, hydroxy, -NO2, Represent -NH 2 , -COOH or halogen (especially -F, -Cl, -Br),
  • R 8 is (optionally fluorinated) Ci 1 0-alkyl, (optionally fluorinated) C2 -io-alkenyl, (optionally fluorinated) C 2 - 1 0-alkynyl, or (optionally fluorinated) C4-io cycloalkyl- ; wherein one or none of the substituents R 1 and R 3 represents -L- # 1,
  • L is the linker and # 1 is the bond to the binder or derivative thereof,
  • R 9 is -H, -F, -CH 3 , -CF 3 , -CH 2 F or -CHF 2 ; wherein -MOD - (NR 10 ) n - (GI) o -G2-G3, wherein
  • R 10 is -H or C 1 -C 3 -alkyl
  • G represents -NHCO-, -CONH-, or ⁇ / (where if Gl is -NHCO-
  • n 0 or 1
  • 0 is 0 or 1
  • G2 is a straight-chain and / or branched hydrocarbon group having 1 to 10 carbon atoms, which is mono- or polysubstituted by one or more of
  • NH2, -NH-CNNH2, sulfonamide, sulfone, sulfoxide, or sulfonic acid can
  • Sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted
  • G3 represents -H or -COOH
  • group -MOD preferably has at least one group -COOH; and their salts, solvates and salts of the solvates.
  • Xi N, N X 2 and X 3 is C;
  • Xi N, X 2 is C and X 3 is N;
  • X 1 is CH or CF, X 2 is C and X 3 is N; or
  • Xi is CH or CF, X 2 is N and X 3 is C;
  • R 1 is -H, -L- # 1, -MOD or - (CH 2 ) 0 - 3 Z, wherein Z is -H, -NHY 3 , -OY 3 , -SY 3 , halogen, -CO-NY'Y 2 , or is -CO-OY 3 ,
  • Y 1 and Y 2 are independently -H, -NH 2, - (CH 2 CH 2 O) 0-3 - (CH 2) 0 - 3.
  • Z' represents wherein Z '- H, -NH 2, -S0 3 H, -COOH, -NH -CO-CH 2 -CH 2 -CH (NH 2 ) COOH or - (CO-NH-CHY 4 ) i_ 3 COOH; where W represents -H or -OH,
  • Y 4 is linear or branched, optionally substituted by-NHCONH 2 , Ci-6 alkyl or optionally substituted by -NH 2 substituted aryl or benzyl;
  • R 2 represents -H, -CO-CHY 4 -NHY 5 or - (CH 2 ) 0 - 3 Z,
  • Y 4 is linear or branched, optionally substituted by -NHCONH 2 ,
  • Ci-6 is alkyl or optionally substituted with -NH 2 substituted aryl or benzyl and Y 5 "
  • R 3 represents -L- # l, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, preferably a Ci-io alkyl, Cö-io-aryl or C6-io-aralkyl, Cs-io-heteroalkyl, Ci-io alkyl-0-C6-io-aryl or C5-1 0- heterocycloalkyl group with 1-3 -OH groups, 1-3 Halogen atoms, 1-3 halogenated alkyl groups (each having 1-3 halogen atoms), 1-3 -O-alkyl groups, 1-3 -SH groups, 1-3 -S-alkyl groups, 1-3 -O-CO- Alkyl groups, 1-3 -O-CO-NH-alkyl groups, 1-3 -NH-CO-alkyl groups, 1-3 -NH-CO-alkyl groups, 1-3 -
  • R 5 is -H, -MOD, -NH 2 , -NO 2 , halogen (especially -F, -Cl, -Br), -CN, CF 3 , -OCF 3 , -CH 2 F, -CH 2 F, -SH or - (CH 2 ) 0 - 3 Z, where Z is -H, -OY 3 , -SY 3 , halogen, -NHY 3 , -CO-NY'Y 2 , or -CO-OY 3 ,
  • Y 1 and Y 2 are independently -H, -NH 2 , or - (CH 2 ) o-3Z ', and Y 3 is -H or - (CH 2 V 3 Z', wherein Z 'is -H, -SO 3 H, Represents -NH 2 or -COOH;
  • R 6 and R 7 independently of one another represent -H or halogen (especially -F, -Cl, -Br),
  • R 8 represents (optionally fluorinated) C 1-10 alkyl; wherein one or none of the substituents R 1 and R 3 represents -L- # 1,
  • L is the linker and # 1 is the bond to the binder or derivative thereof,
  • R 9 is -H, -F, -CH 3 , -CF 3 , -CH 2 F or -CHF 2 ; wherein -MOD is -CH 2 -S x - (CH 2 ) o-4-CHY 5 -COOH, where x is 0 or 1, and Y 5 is -H or -NHY 6 , wherein Y 6 is -H or -COCH 3 and their salts, solvates, salts of solvates and epimers.
  • R 1 and R 5 are H or -L- # 1;
  • R 2 represents H;
  • R 4 is the group of the formula R 21 - (CO) ( 0 -i) - (P 3) ( o-2) -P 2 -NH-CH (CH 2 CONH 2 ) -CO- or the cathepsin-cleavable group of the formula R 21 - (CO) (oi) - (P3) (0 - 2) -P2-, where P2 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys Arg, citrulline, and His; P3 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys Arg, citrulline, and His;
  • the antibody-drug conjugates (ADCs) according to the invention preferably have the following formula VIII:
  • n is 0 or 1;
  • X is -CONH 2 or -COOH
  • L a represents a self-immolative linker
  • L c represents a linker
  • Ai is a radical other than one of Gly, Pro, Ala, Val, Nva, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg , Citrulline and His are derived;
  • A2 is a radical other than one of Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg , Citrulline and His or one of the respective N-alkyl-amino acids, preferably N-methyl-amino acids derived (if more than one P3 is present, P3 may therefore have different meanings)
  • Dl is a compound of formula III;
  • R is Zi- (CO) q-, where q is 0 or 1 and Zi is a Ci-io alkyl, Cs-io-aryl or C6-io-aralkyl, Cs-io-heteroalkyl, Ci-io -Alkyl-0-C6-io-aryl, Cs-io-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, Cs-io-heteroaryl-alkoxy, Ci-io-alkoxy, C6-io-aryloxy or C6-io-aralkoxy, C5-10-heteroalkoxy, Ci-io-alkyl-0-C6-io-aryloxy, Cs-io-heterocycloalkoxy group which is mono- or polysubstituted with - NH 2 , -NH Alkyl, -N (alkyl) 2 , -NH-CO-alkyl, -
  • the antibody prodrug conjugates (APDCs) according to the invention preferably have the following formula IX:
  • n 0 or 1:
  • X is -CONH 2 or -COOH
  • L a represents a self-immolative Unker
  • L ⁇ represents a linker
  • Ai is a radical other than one of Gly, Pro, Ala, Val, Nva, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg , Citrulline and His are derived;
  • Dl is a compound of formula III
  • R is Zi (CO) q-, where q is 0 or 1 and Zi is a C-10-alkyl, Cs-io-aryl or C6-io-aralkyl, C5-io-heteroalkyl, Ci-io Alkyl-0-C6-io-aryl, Cs-io-heterocycloalkyl, heteroaryl, heteroaryl-alkyl, Cs-io-heteroaryl-alkoxy, Ci-10-alkoxy, C6-io-aryloxy or C6-io-aralkoxy, C5-10-heteroalkoxy, Ci-io-alkyl-0-C6-io-aryloxy, Cs-io-heterocycloalkoxy group which is mono- or polysubstituted with -NH 2 , -NH Alkyl, -N (alkyl) 2 , -NH-CO-alkyl, -N (alkyl) -
  • these methods also include enzymatic conjugation methods using, for example, transglutaminases (TGases), glycosyltransferases or the formylglycine-generating enzyme (Sochaj et al., Biotechnology Advances 3JL 775-784, (2015)).
  • TGases transglutaminases
  • glycosyltransferases glycosyltransferases
  • formylglycine-generating enzyme Sochaj et al., Biotechnology Advances 3JL 775-784, (2015).
  • conjugate site-specific binder conjugates of the kinesin spindle protein inhibitor in which the kinesin spindle protein inhibitors are conjugated to glutamine side chains of the binders can be provided.
  • the binder When the binder is an antibody, it includes an acceptor glutamine, preferably in the constant region.
  • acceptor glutamines can be introduced by mutation of suitable positions to glutamine (for example the N297Q heavy chain mutation, Kabat EU numbering) or by generation of deglycosylated or aglycosylated antibodies (for example by enzymatic deglycosylation by PNGase F or by N297X mutation) heavy chain, Kabat EU numbering (X can here be any amino acid except N)).
  • glutamine residue Q295 Kabat EU numbering
  • all antibodies described in this invention also include aglycosylated variants of these antibodies, either by deglycosylation by PNGase F or by mutation of N297 (Kabat EU numbering) (Kabat numbering system of antibodies, see Kabat et al., Sequences of Proteins of Immulological Interest , 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD. (1991)) of the heavy chain to any amino acid except N.
  • all antibodies described herein also contain variants of the described antibodies, which contain by engineering one or more acceptor glutamine residues for transglutaminase-catalyzed reactions.
  • Transglutaminases which also include bacterial transglutaminase (BTG) (EC 2.3.2.13), are a family of enzymes that cause the formation of a covalent bond between the ⁇ -carbonyl-amide group of glutamines and the primary amine group catalyze lysines. Because such transglutaminases also accept substrates other than lysine as an amine donor, they have been used to modify proteins, including antibodies, to appropriate acceptor glutamines (Jeger et al., Angewandte Chemie International Ed.
  • the bacterial transglutaminase can be used for the conjugation of an amine donor substrate, for example, an active-linker construct, to an acceptor glutamine residue of an antibody.
  • acceptor glutamines can be introduced by engineering the antibody by mutations or by generating aglycosylated antibodies.
  • aglycosylated antibodies can be introduced by deglycosylation using N-glycosidase F (PNGase F) or by mutating N297 of the heavy chain glycosylation site (Kabat EU numbering) to any amino acid except N.
  • 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. 2J, 5-13 (2010)).
  • the in vivo cleavable linkers have an in vivo cleavable group, again distinguishing between chemically in vivo cleavable and enzymatically cleavable groups.
  • “Chemically in vivo cleavable” or “enzymatically cleavable in vivo” means that Groups in the bloodstream are stable and only at or in the target cell by the altered chemical or enzymatic environment (lower pH, increased glutathione concentration, presence of lysosomal enzymes such as legumain, cathepsin or plasmin, or glyosidases such as ⁇ - Glucuronidases), so as to release the low molecular weight KSP inhibitor or a derivative thereof.
  • the chemically in vivo cleavable groups are in particular disulfide, hydrazone, acetal and aminal; the enzymatically in vivo cleavable groups are in particular 2-8-Oligopeptidolit, in particular a dipeptide group or glycosides.
  • Peptide cleavage sites are disclosed in Bioconjugate Chem. 2002, 13, 855-869, and Bioorganic & Medicinal Chemistry Letters 8 (1998) 3341-3346 and Bioconjugate Chem. 1998, 9, 618-626. These include e.g.
  • self-immolative linker elements SIG eg in the above formula IIa or La in the above formulas VIII and IX
  • active ingredient can be optionally incorporated (anticancer agents in Medicinal Chemistry, 2008, 8, 618-637).
  • the release of the active substance can take place according to various mechanisms, for example after initial enzymatic release of a nucleophilic group by subsequent elimination via an electronic cascade (Bioorg.Med.Chem., 1999, 7, 1597, J.Med.Chem., 2002, 45 , 937; Bioorg. Med. Chem., 2002, 10, 71) or by cyclization of the corresponding linker element (Bioorg. Med.
  • the in vivo stable linkers are characterized by a high stability (less than 5% metabolites after 24 hours in plasma) and do not have the above-mentioned chemically or enzymatically cleavable groups in vivo.
  • the linker -L- (as well as Lc in formula VIII and Lb in formula IX) preferably has one of the following basic structures (i) to (iv):
  • the coupling may be to a tyrosine residue, glutamine residue or an unnatural amino acid of the antibody.
  • the unnatural amino acids may include, for example, aldehyde or keto groups (such as formyl glycine) or azide or alkyne groups (see Lan & Chin, Cellular Incorporation of Unnatural Amino Acids and Bioorthogonal Labeling of Proteins, Chem.Rev. 2014, 114, 4764-4806).
  • the administration of a conjugate according to the invention having a linker basic structure (iii) and coupling of the linker to a cysteine or lysine residue of the antibody leads by metabolization to cysteine or lysine derivatives of the following formulas:
  • LI is in each case bound to the low molecular weight KSP inhibitor, for example a compound of the formula (III) or (IIa), (IIb), (IIc), (Ild), (Ile), (IIIf), or (IV) in which -L- # 1 represents one of the two above radicals derived from lysine or cysteine, respectively.
  • linker basic structure (i) when bound to the position R4, in particular when m 0.
  • L2 is preferably derived from a group reactive with the sulfhydryl group of the cysteine.
  • groups include haloacetyls, maleimides, aziridines, acryloyls, arylating compounds, vinylsulfones, pyridyl disulfides, TNB-thiols and disulfide reducing agents.
  • These groups typically react electrophilically with the sulfhydryl bond to form a sulfide (eg, thioether) or disulfide bridge. Preference is given to stable sulfide bridges.
  • L2 is preferable
  • # 1 denotes the point of attachment to the sulfur atom of the antibody
  • # 2 denotes the point of attachment to the group L 1
  • R 2 is -COOH, -COOR, -COR, -CONHR, -CONR 2 (each R is Cl-3-alkyl), -CONH 2, preferably -COOH.
  • L2 is:
  • the bonds to a cysteine residue of the antibody are preferably more than 80%, more preferably more than 90% (in each case based on the total number of links of the linker to the antibody), particularly preferably in one of the two structures of the formula A3 or A4 ago.
  • the structures of the formula A3 or A4 are generally present together, preferably in a ratio of 60:40 to 40:60, based on the number of bonds to the antibody. The remaining bonds are then in the structure
  • LI is preferably represented by the formula
  • R 10 is -H, -NH 2 or C 1 -C 3 -alkyl
  • Gl represents -NHCO-, -CONH- or ⁇ / (R 1 U is preferably not -NH 2 , if
  • n 0 or 1
  • 0 is 0 or 1
  • G2 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms of arylene groups and / or straight-chain and / or branched and / or cyclic alkylene groups which is mono- or polysubstituted by one or more of the groups -O-, -S-, -SO-, -SO2-, -NRY-, -
  • NRYCO- NRYCO-, -C (NH) NRy-, -CONRY-, -NRYNRY-, -SO2NRyNRy-, -CONRYNRy-, (wherein R y is -H, phenyl, C 1 -C 4 -alkyl, C 2 -C 4 -Q- Alkenyl, or C2-C1 represents Q-alkynyl, each with
  • NHCONH 2 , -COOH, -OH, -NH 2 , -NH-CNNH 2, sulfonamide, sulfone, sulfoxide, or sulfonic acid), -CO-, -CR x N-O- (where Rx H, Ci - C3-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 -S02- may be interrupted (preferably
  • hydrocarbon chain including the side chains, if present, may be substituted by -NHCONH 2 , -COOH, -OH, -NH 2 , -NH-CNNH 2, sulfonamide, sulfone, sulfoxide, or sulfonic acid.
  • G2 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms of arylene groups and / or straight-chain and / or branched and / or cyclic alkylene groups which is mono- or polysubstituted by one or more of the groups -O-, -S-, -SO-, -SO 2 -, -NH-, - CO-, -NHCO-, -CONH-, -NMe-, -NHNH-, -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 - N N-CO-
  • OH, -NH2, -NH-CN H2, sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted.
  • hydrocarbon chain including the side chains if present, with -NHCONH 2 , -COOH, -OH, -NH 2 , -NH-CN H 2 , sulfonamide, sulfone, sulfoxide, or sulfonic acid may be substituted.
  • Rx is H, C-C3-alkyl or phenyl.
  • # 1 is the binding to the KSP inhibitor or prodrug and # 1 is the binding to the coupling clot to the antibody (e.g., L2).
  • a straight-chain or branched hydrocarbon chain of aryl groups and / or straight-chain and / or branched and / or cyclic alkylene groups generally comprises an .alpha.,. Omega.-divalent alkyl radical with the respectively indicated number of carbon atoms. Examples which may be mentioned by way of example and are preferably: methylene, ethane-1,2-diyl (1,2-ethylene), propane-1,3-diyl (1,3-propylene), butane-1,4-diyl (1,4-diyl).
  • Butylene pentane-l, 5-diyl (1,5-pentylene), hexane-1,6-diyl (1,6-hexylene), heptane-l, 7-diyl (1,7-hexylene), octane l, 8-diyl (1,8-octylene), nonane-l, 9-diyl (1,9-nonylene), decane-l, 10-diyl (1,10-decylene).
  • alkylene groups in the hydrocarbon chain can also be branched, ie one or more H atoms of the abovementioned linear alkylene groups can optionally be substituted by C 1-10 -alkyl groups and thus form side chains.
  • the hydrocarbon chain can furthermore contain cyclic alkylene groups (cycloalkanediyl), for example 1,4-cyclohexanediyl or 1,3-cyclopentanediyl. These cyclic groups may be unsaturated.
  • aromatic groups (arylene groups) may be present in the hydrocarbon group, for example phenylene.
  • one or more H atoms may optionally be substituted by C 1-10 -alkyl groups. It is thus formed a hydrocarbon chain, which is optionally branched. This hydrocarbon chain has a total of 0 to 100 carbon atoms, preferably 1 to 50, particularly preferably 2 to 25 carbon atoms.
  • the side chains can, if present, with -NHCONH 2 , -COOH, -OH, -NH 2 , -NH-CN H 2 ,
  • the hydrocarbon chain can be monosubstituted or polysubstituted by identical or different substituents by -O-, -S-, SO-, -SO 2 -, -NH-, -CO-, -NHCO-, -CONH-, -NMe-, -NHNH-, -SO2NHNH-, -CONHNH- and a 5 to 1 Ogliedriger, aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from N, O and S, -SO- or -S02- be interrupted (preferably
  • the linker corresponds to the following formula:
  • ⁇ represents the binding to the drug molecule or prodrug and ⁇ ⁇ represents the binding to the binder peptide or protein, and LI and L2 have the meanings mentioned above.
  • LI has the formula -NR 1 l B-, where
  • R 11 represents -H or -NH 2 ;
  • B represents - [(CH 2 ) x - (X 4 ) y ] w - (CH 2 ) z -,
  • Linker L preferred according to the invention has the following formula:
  • # 3 represents the binding to the Wirkstoffitnolekül or prodrug
  • # 4 represents binding to the binder peptide or protein
  • R 1 1 is -H or -NH 2;
  • B represents - [(CH 2 ) x - (X 4 ) y ] w - (CH 2 ) z -,
  • z 1 to 5; and X 4 is -O-, -CONH-, -NHCO- or represents.
  • linkers are preferred, where the linker Li is one of the following groups:
  • ⁇ represents the binding to the drug molecule
  • ⁇ ⁇ represents the binding to the antibody
  • 1S0C3H 7 represents an isoPropyl radical
  • linkers are particularly preferably coupled in conjugates of the formula (IIa) in which the linker attaches to R 4 by substitution of an H atom on R 1 or in conjunction with a cleavable linker SG 1, ie R 1 -L- # 1 or R 4 SG1-L- # 1, where # 1 represents the binding to the antibody.
  • the following linkers are preferred according to the invention:
  • 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:
  • # 1 denotes the point of attachment to the sulfur atom of the antibody
  • # 2 denotes the point of attachment to the group L 1
  • R 22 is -COOH, -COOR, -COR, -CONR 2 , -CONHR (each R is Cl-3-alkyl), -CONH 2 , preferably -COOH.
  • the structures of the formula A5 or A6 are generally present together, preferably in a ratio of 60:40 to 40:60, based on the number of bonds to the antibody. The remaining bonds are then in the structure
  • linker -L- attached to a cysteine side chain or cysteine residue have the following formula:
  • ⁇ represents the binding to the drug molecule or prodrug
  • ⁇ ⁇ represents the binding to the binder peptide or protein
  • n 0, 1, 2, or 3;
  • n 0, 1 or 2;
  • p is 0 to 20;
  • o 0 or 1
  • G3 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms
  • Arylene groups and / or straight-chain and / or cyclic alkylene groups which is mono- or polysubstituted by one or more of the groups -O-, -S-, -SO-, SO 2, -NH-, -CO-, -NHCO-, - CONH , -NMe-, -NHNH-, -SO 2 NHNH-, -CONHNH- and a 3 to 10-membered (preferably 5 to 10-membered), aromatic or non-aromatic heterocycle having up to 4 heteroatoms selected from N, O and S, -SO- or -S02- may be interrupted (preferably - N N-CO-
  • NH2, -NH-CN H2, sulfonamide, sulfone, sulfoxide or sulfonic acid may be substituted.
  • n 1;
  • n 0;
  • 0 is 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 S- (CO) m-LI-L2-Sections are the following, where r is a number from 0 to 20, preferably from 0 to 15, particularly preferably from 1 to 20, particularly preferably from 2 to 10 has:
  • the bonds to a cysteine residue of the binder are preferably more than 80%, more preferably more than 90% (in each case based on the total number of bonds of the linker to the binder), particularly preferably in one of the two structures of the formula A7 or A8 before.
  • the structures of the formula A7 or A8 are generally present together, preferably in a ratio of 60:40 to 40:60, based on the number of bonds to the binder. The remaining bonds are then in the structure
  • conjugates with corresponding linkers have the following structures, wherein XI is CH, X2 C, and X3 N, and LI has the abovementioned meaning, L2 and L3 has the same meaning as LI, AKl is an antibody having a Cysteine residue is attached, and n is a number from 1 to 10.
  • AKI is a human, humanized or chimeric monoclonal antibody.
  • Particularly preferred is an aglycosylated anti-TWEAKR antibody which specifically binds to amino acid D at position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular anti-TWEAKR antibody TPP-2658.
  • linker is bound to a lysine side chain or a lysine residue
  • the same linker as described above can be used for coupling to a Cy stein side chain
  • L2 is preferably a carbonyl group (the coupling is carried out, for example via a corresponding activated carboxylic acid).
  • conjugates having the basic structure (i) have one of the following structures, wherein XI is CH, X2C, and X3 is N, L4 has the same meaning as LI, AKI is an aglycosylated anti-TWEAKR antibody having a cysteine residue is attached, and n is a number from 1 to 10, and the hydrogen atom in position according to formula IIa (ie in the group -NH2) by a legumain cleavable group of the formula R 21 -CO-P3-P2-NH-CH ( CH 2 CONH 2 ) -CO- is replaced :.
  • R is a C 1-10 -alkyl, C 6-10 -aryl or C 6-10 -aralkyl, C 3-10 -heteroalkyl-, C 1-10 -alkyl-O-C 6-10 -aryl, C 5-10 -heterocycloalkyl-, C 1-10 alkoxy, C 6-10 aryloxy or C 6-10 aralkoxy, C 5-10 heteroalkoxy, C 1-10 -alkyl-O-C 6-10 aryloxy, C 1-10 heterocycloalkoxy which may be mono- or polysubstituted by --NFh, -SO3H, -COOH, -SH, or -OH: P2 Single bond or an amino acid selected from Gly, Pro, Ala, Val, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, and His;
  • P3 is a single bond or an amino acid selected from Gly, Pro, Ala, Val, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, and His.
  • anti-TWEAKR antibody which specifically binds to amino acid D at position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the aglycosylated anti-TWEAKR antibody TPP-2658.
  • the literature discloses various possibilities of covalent coupling (conjugation) of organic molecules to binders such as e.g. Antibodies in a conjugation site specific manner (see, for example, Sochaj et al., Biotechnology Advances, 3JL 775-784, (2015), Panowski et al., MAbs 6, 34-45 (2014)).
  • Preferred according to the invention is the conjugation of the KSP inhibitors or prodrugs to an antibody via acceptor glutamine residues of the antibody using transglutaminase.
  • acceptor glutamine residues can be generated via engineering of the antibody or by mutations that produce aglycosylated antibodies.
  • Suitable linkers are used for coupling (conjugation).
  • Suitable linker structures are those which have a free amine donor functionality, which is a suitable substrate for the transglutaminase.
  • the linkage of the linker to the antibody can be done in many ways.
  • the linker in a transglutaminase-catalyzed conjugation, has one of the above basic structures (i) to (iv), wherein LI, SG, SGI and m have the abovementioned meanings, but L2 preferably represents one of the following groups:
  • R is -CONHalkyl, -CONH 2 , in which
  • # 2 represents the point of attachment to the glutamine residue of the binder.
  • Ry is H or -NHCOMe.
  • KSP inhibitor conjugates wherein AK (AKi, AK2, AK3) for binders or a derivative thereof (preferably for an antibody), and n for a number from 1 to 50, preferably 1.2 to 20 and more preferably 2 to 8 stands.
  • AKi is preferably an antibody linked to the KSP inhibitor via a cysteine residue
  • AK 2 is preferably an antibody which is bound via a lysine residue to the KSP inhibitor
  • AK3 is preferably an antibody which is bound via a glutamine residue to the KSP inhibitor.
  • a binder or antibody are preferably the in uses.
  • the conjugates according to the invention are prepared by initially providing the low molecular weight KSP inhibitor or prodrug thereof with a linker. The intermediate thus obtained is then reacted with the binder (preferably antibody).
  • cysteine residue For coupling to a cysteine residue it is preferred to use one of the following compounds with the cysteine-containing binder, e.g. an antibody that may have been partially reduced, implemented:
  • R represents -H or -COOH
  • K represents a linear or branched cis-alkyl which is optionally substituted by C 1 -C 6 -alkoxy or -OH, and
  • XI CH, X2 C, and X3 is N, SGI, LI, L2, L3 and L4 have the same meaning as described above.
  • the hydrogen atom in position R 1 according to formula IIa (ie in the group - NH 2 ) can be represented by the group of the formula R 21 - (CO) (oi) - (P 3 ) (o-2) -P 2 -NH-CH (CH 2 CONH 2 ) -CO- or the cathepsin-cleavable group of the formula R 21 - (CO) oi ) - (P 3) (i-2 ) -P 2 - wherein P2 is an amino acid selected from Gly, Pro, Ala, Val, Nva, Leu, He, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gin, Asp, Glu, Lys, Arg, Citrulline, and His is;
  • R is a Ci-io-alkyl, C6-io-aryl or C6 io-aralkyl, Cs-io-heteroalkyl, Ci-io-alkyl-0-C6-io-aryl, C5-io-heterocycloalkyl , C 1-10 -alkoxy-, C 1-10 -aryloxy- or C 6-10 -alkoxy-, C 5-10 -haloalkoxy-, C 1-10 -alkyl-O-C 20 -alkyloxy-, C 1-10 -heterocycloalkoxy- Group, which may be substituted one or more times with - NH2, -SO3H, -COOH, -SH, or -OH.
  • succinimide-linked ADCs can be converted after conjugation into the open-chain succinic acid amides which have a favorable stability profile.
  • This reaction can be carried out at pH 7.5 to 9, preferably at pH 8, at a temperature of 25 ° C to 37 ° C, e.g. by stirring.
  • the preferred stirring time is 8 to 30 hours.
  • XI represents CH, X 2 C, and X 3 represents N; SGI and LI have the same meaning as described above, and L2, L3 and L4 have the same meaning as LI; and R and K have the same meaning as described above.
  • AK1 is a cysteine-linked aglycosylated anti-TWEAKR antibody, and AK2 is a lysine-linked, aglycosylated anti-TWEAKR antibody.
  • AK1 and AK2 provide an aglycosylated anti-TWEAKR antibody that specifically binds to amino acid D at position 47 (D47) of TWEAKR (SEQ ID NO: 169), in particular the aglycosylated anti-TWEAKR antibody TPP-2658. Further definitions
  • transglutaminase also used interchangeably as “TGase” or “TG” is understood to be an enzyme which has the ability to express proteins through an acyl-transfer reaction between the ⁇ -carboxamide group of peptide-bound glutamine and the ⁇ To link amino group of lysine or a structurally related primary amine, such as an aminopentyl group or, for example, a peptide-bound lysine, resulting in an 8- (7-glutamyl) lysine isopeptide bond.
  • TGases include, but are not limited to, bacterial transglutaminase ( BTG) such as the enzyme with EC reference number 2.3.2.13 (protein glutamine-y-glutamyltransferase).
  • acceptor glutamine when referring to an amino acid residue of an antibody, means a glutamine residue which, under appropriate conditions, is recognized by a transglutaminase and transglutaminase catalyzed by a reaction between the same glutamine and a lysine or a structurally related primary amine, such as, for example an aminopentyl group, can be linked to this.
  • the acceptor glutamine is a surface-exposed glutamine.
  • amino acid modification or “mutation” herein is meant an amino acid substitution, insertion, and / or a deletion in a polypeptide sequence.
  • the preferred amino acid modification is here a substitution.
  • amino acid substitution or “substitution” herein is meant an exchange of an amino acid at a given position in a protein sequence with another amino acid.
  • substitution Y50W describes a variant of a parent polypeptide in which the tyrosine at position 50 is replaced by a tryptophan.
  • a “variant" of a polypeptide describes a polypeptide having an amino acid sequence that is substantially identical to a reference polypeptide, typically a native or “parent” polypeptide.
  • the polypeptide variant may have one or more amino acid exchanges, deletions, and / or insertions at particular positions in the native amino acid sequence.
  • conjugate site-specific conjugate describes a conjugate of a binder, preferably an antibody, and a moiety, preferably a linker drug moiety, wherein the binder is functionalized at one or more defined positions, preferably glutamine residues.
  • TGases including bacterial Transglutaminase (BTG) (EC 2.3.2.13), show strong specificity in the recognition of glutamine protein substrates and can catalyze "conjugate site-specific conjugation”.
  • homogeneous conjugate or “homogeneous ADC” describes a mixture of conjugate site-specific conjugates wherein at least 60, 70, 80, or 90% of the binders have the same number of conjugated residues per binder. In the case of an antibody, this number should be an even number, preferably 2 or 4.
  • binder is broadly understood to mean a molecule which binds to a target molecule present on a particular target cell population to be targeted with the binder-drug conjugate includes, for example, lectins, proteins that bind certain sugar chains, or phospholipid-binding proteins, such as high molecular weight proteins (binding proteins), polypeptides or peptides (binding peptides), non-peptidic (eg, aptamers (US5,270,163) review articles by Keefe AD Rev.
  • lectins proteins that bind certain sugar chains
  • phospholipid-binding proteins such as high molecular weight proteins (binding proteins), polypeptides or peptides (binding peptides), non-peptidic (eg, aptamers (US5,270,163) review articles by Keefe AD Rev.
  • Binding peptides are e.g. Ligands of a ligand-receptor pair, e.g.
  • VEGF of the ligand receptor pair VEGF / KDR such as transferrin of the ligand receptor pair transferrin / transferrin receptor or cytokine / cytokine receptor, such as TNF alpha of the ligand receptor pair TNFalpha / TNF alpha receptor.
  • the "binder” may contain an acceptor glutamine residue which may be functionalized by a transglutaminase (TGase) including bacterial transglutaminase (BTG) (EC 2.3.2.13) .
  • TGase transglutaminase
  • BCG bacterial transglutaminase
  • This acceptor glutamine may either naturally be present in the binder or it will
  • An acceptor glutamine may be genreated via insertion of a glutamine residue at a suitable position (eg, via a fusion tag containing an acceptor glutamine, or via a mutation of a suitable position to a glutamine residue), or an acceptor glutamine.
  • Glutamine is generated by a mutation of any amino acid that causes a particular glutamine residue not previously recognized by the transglutaminase to become an acceptor glutamine, or an acceptor glutamine is genered by a change in a post-translational modification (eg, glycosylation), which change has the effect of turning a naturally occurring glutamine, not previously recognized by a transglutaminase, into an acceptor glutamine.
  • a post-translational modification eg, glycosylation
  • the binder is an antibody, it contains an acceptor glutamine, preferably in the constant region.
  • acceptor glutamines can be generated by mutations of suitable positions to glutamine (eg the mutation N297Q, Kabat EU numbering) or by the generation of deglycosylated or aglyclosylated antibodies (eg by deglycosylation by PNGase F or by the mutation N297X, Kabat EU numbering) , In the latter case of a deglycosylated or aglycosylated antibody, glutamine residue Q295 (Kabat EU numbering) of the heavy chain becomes an acceptor glutamine. Particularly preferred is an antibody containing the mutation N297A or N297Q (Kabat EU numbering).
  • aglycosylated antibody or "deglycosylated antibody” is used herein to define an antibody or antibody derivative that contains an FC region that lacks the glycans attached to the conserved N-glycosylation site in the CH2 domain.
  • aglycosylated antibodies can be made by mutation of the heavy chain glycosylation site N297 (Kabat Eu numbering) or by expression of antibodies in expression systems lacking the ability to glycosylate. Methods for antibody deglycosylation are well known (e.g., Winkelhake & Nicolson (1976), J Biol Chem. 251 (4): 1074-80)).
  • deglycosylated antibodies can be generated by enzymatic deglycosylation by PNGase F.
  • aglycosylated antibodies can be obtained by expression in prokaryotic hosts. Suitable prokaryotic hosts include but are not limited to E. coli, Bacillus subtilis, Salmonella typhimurium, and some species of the genus Pseudomonas, Streptomyces, and Staphylococcus.
  • aglycosylated antibodies can be obtained by the use of mammalian cell expression systems together with the glycosylation inhibitor tunicamycin (Nose & Wigzell (1983), Proc Natl Acad. USA, 80 (21): 6632-6).
  • tunicamycin Nose & Wigzell (1983), Proc Natl Acad. USA, 80 (21): 6632-6.
  • the modification is the prevention of glycosylation at the conserved N-glycosylation site N297 (Kabat numbering) of the heavy chain in
  • the literature also discloses various options of conjugate site-specific covalent coupling (conjugation) of organic molecules to antibodies. Particular attention is paid in this regard to the conjugation of toxophores to antibodies via two or four acceptorglutamine residues of the antibody.
  • Various possibilities of covalent coupling (conjugation) of organic molecules to antibodies are known from the literature.
  • the conjugation of the toxophore to the antibody is preferably via one or more sulfur atoms of cysteine residues of the antibody and / or via one or more NH groups of lysine residues of the antibody.
  • a "target molecule” is broadly understood to be a molecule present in the target cell population, and may be a protein (eg, a growth factor receptor) or a non-peptidic molecule (eg, a sugar or phospholipid) Receptor or an antigen.
  • extracellular target molecule describes a cell-bound target molecule located on the outside of a cell or the part of a target molecule that is on the outside of a cell, ie, a binder can bind to an extracellular target molecule on an intact cell
  • An extracellular target molecule can be anchored in the cell membrane or be part of the cell membrane
  • the person skilled in the art knows of methods for identifying extracellular target molecules For proteins this can be done by determining the transmembrane domain (s) and the orientation of the protein in the membrane Information is usually stored in protein databases (eg SwissProt).
  • cancer target molecule describes a target molecule that is more abundant on one or more types of cancer cells compared to non-cancerous cells of the same tissue type, Preferably, the cancer target molecule is on one or more cancer cell types compared to non-cancer cells of the same tissue type selectively present, selectively expressing 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.
  • the binder can be linked via a linkage with the linker.
  • the linkage of the binder can be effected by means of a heteroatom of the binder.
  • Heteroatoms of the invention which can be used for linking are sulfur (in one embodiment via a sulfhydryl group of the binder), oxygen (according to the invention by means of a carboxyl or hydroxyl group of the binder) and nitrogen (in one embodiment via a primary or secondary amine group or amide group of the binder).
  • These heteroatoms can be natural Binder be present or be introduced by chemical or molecular biological methods.
  • the linkage of the binder with the toxophore has only a small influence on the binding activity of the binder to the target molecule. In a preferred embodiment, the linkage has no influence on the binding activity of the binder to the target molecule.
  • an immunoglobulin molecule preferably comprises a molecule having four polypeptide chains, two heavy chains (H chains) and two light chains (L chains), which are typically linked by disulfide bridges.
  • Each heavy chain comprises a heavy chain variable domain (abbreviated VH) and heavy chain constant domain.
  • the heavy chain constant domain may include three domains CHI, CH2 and CH3.
  • Each light chain comprises a variable domain (abbreviated VL) and a constant domain.
  • the constant domain of the light chain comprises a domain (abbreviated to CL).
  • the VH and VL domains can be further subdivided into regions of hypervariability, also called complementarity determining regions (abbreviated to CDR) and regions of lower sequence variability (FR).
  • CDR complementarity determining regions
  • FR regions of lower sequence variability
  • Each VH and VL region typically consists of three CDRs and up to four FRs. 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, e.g. Rabbit, llama, camel, mouse, or rat. In one embodiment, the antibody is of human or murine origin.
  • An antibody can e.g. be humane, humanized or chimeric.
  • 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 and may also be aglycosylated.
  • modified intact antibody refers to intact antibodies that have been fused to another non-antibody polypeptide or protein via their amino terminus or carboxy-terminus via a covalent bond (eg, a peptide linkage) modified to introduce reactive cysteines at defined sites to facilitate coupling to a toxophore (see Junutula et al., Nat Biotechnol., 2008 Aug; 26 (8): 925-32).
  • human antibody refers to antibodies that can be obtained from a human or are synthetic human antibodies
  • a "synthetic” human antibody is an antibody that is available in part or in full as a whole from synthetic sequences in silico that are based on the Analysis of human antibody sequences.
  • a human antibody can e.g. be encoded by a nucleic acid isolated from a library of antibody sequences of human origin. An example of such antibodies is in Söderlind et al., Nature Biotech. 2000, 18: 853-856.
  • Such "human” and “synthetic” antibodies also include aglycosylated variants prepared either by deglycosylation by PNGaseF or by mutation of N297 (kabat numbering) of the heavy chain to any other amino acid.
  • 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.
  • Such "humanized” and “chimeric” antibodies also include aglycosylated variants prepared by either deglycosylation by PNGaseF or by mutation of N297 (kabat numbering) of the heavy chain to any other amino acid.
  • 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, which are considered CDR1, CDR2 and CDR3.
  • Each CDR region may comprise amino acids as defined by Kabat and / or amino acids of a hypervariable loop defined by Chotia.
  • the Kabat definition includes, for example, the region of approximately amino acid position 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) of the variable light chain and 31-35 (CDR1), 50-65 (CDR2). and 95-102 (CDR3) variable heavy chain (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed.
  • Chotia includes, for example, the region of approximately amino acid position 26-32 (CDR1), 50-52 (CDR2) and 91-96 (CDR3) of the variable light chain and 26-32 (CDR1), 53-55 (CDR2). and 96-101 (CDR3) of the variable heavy chain Chothia and Lesk; J Mol Biol 196: 901-917 (1987)).
  • a CDR may comprise amino acids from a CDR region as defined by Kabat and Chotia.
  • antibodies can be divided into different classes. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG and IgM, several of which can be broken down into other subclasses. (Isotypes), e.g. IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2.
  • the heavy chain constant domain corresponding to the different classes are referred to as [alpha / a], [delta / ⁇ ], [epsilon / ⁇ ], [gamma / ⁇ ] and [my / ⁇ ]. Both the three-dimensional structure and the subunit structure of antibodies are known.
  • the term "functional fragment” or "antigen-binding antibody fragment” of an antibody / immunoglobulin is defined as a fragment of an antibody / immunoglobulin (e.g., the variable domains of an IgG) that still encompasses the antigen-binding domains of the antibody / immunoglobulin.
  • the "antigen binding domain" of an antibody typically comprises one or more hypervariable regions of an antibody, eg the CDR, CDR2 and / or CDR3 region
  • the "framework” or “framework” region of an antibody may also bind to the antibody
  • the antigen binding domain comprises at least amino acids 4 to 103 of the variable light chain and amino acids 5 to 109 of the variable heavy chain, more preferably amino acids 3 to 107 of the variable light chain Chain and 4 to 111 of the variable heavy chain, particularly preferred are the complete variable light and heavy chains, ie amino acids 1 - 109 of the VL and 1 to 113 of the VH (numbering according to WO97 / 08320).
  • “Functional fragments” or “antigen-binding antibody fragments” of the invention do not exhaustively include Fab, Fab ', F (ab') 2 and Fv fragments, diabodies, single domain antibodies (DAbs), linearae antibodies, single chain antibodies (single-chain Fv, abbreviated scFv); and multispecific, such as bi- and tri-specific, antibodies formed from antibody fragments CA K Borrebaeck, editor (1995) Antibody Engineering (Breakthroughs in Molecular Biology), Oxford University Press; R. Kontermann & S. Duebel, editors (2001) Antibody Engineering (Springer Laboratory Manual), Springer Verlag). Antibodies other than "multi-specific” or “multi-functional” are those with identical binding sites.
  • Multispecific antibodies may be specific for different epitopes of an antigen or specific for epitopes of more than one antigen (see, for example, WO 93/17715, WO 92/08802, WO 91/00360, WO 92/05793, Tutt, et al., 1991 , J. Immunol., 147: 60 69; U.S. Patent Nos. 4,474,893; 4,7 14,68 1; 4,925,648; 5,573,920; 5,601,819; or Kostelny et al., 1992, J. Immunol. 148: 1547 1553 ).
  • An F (ab ') 2 or Fab molecule can be designed to reduce or completely prevent the number of intermolecular disulfide interactions that occur between the Chi and CL domains.
  • Epitopic determinants refers to protein determinants that can specifically bind to an immunoglobulin or T cell receptor Epitopic determinants usually consist of chemically active surface groups of molecules such as amino acids or sugar side chains, or combinations thereof, and typically have specific 3-dimensional structural properties such as also specific charge characteristics.
  • “Functional fragments” or “antigen-binding antibody fragments” may be fused to another non-antibody polypeptide or protein via their amino-terminus or carboxy-terminus via a covalent bond (e.g., a peptide linkage). Furthermore, antibodies and antigen-binding fragments can be modified to introduce reactive cysteines at defined sites to facilitate coupling to a toxophore (see Junutula et al., Nat Biotechnol., 2008 Aug; 26 (8): 925-32) ).
  • Polyclonal antibodies can be prepared by methods known to those of ordinary skill in the art.
  • Monoclonal antibodies can be prepared by methods known to those of ordinary skill in the art (Köhler and Milstein, Nature, 256, 495-497, 1975).
  • Humanized human monoclonal antibodies can be prepared by methods known to those of ordinary skill in the art (Olsson et al., Meth Enzymol., 92, 3-16 and Cabilly et al., US 4,816,567 or Boss et al., US 4,816,397).
  • Antibodies of the invention may be obtained from recombinant antibody libraries consisting, for example, of the amino acid sequences of a variety of antibodies generated from a large number of healthy volunteers. Antibodies can also be made by known recombinant DNA technology. The nucleic acid sequence of an antibody can be obtained by routine sequencing, or is available from publicly available databases.
  • an “isolated” antibody or binder has been purified from other components of the cell Contaminating components of a cell that may interfere with a diagnostic or therapeutic use are, for example, enzymes, hormones, or other peptidic or non-peptidic components of a cell an antibody or binder that has been purified to more than 95% by weight of the antibody or binder (determined, for example, by Lowry method, UV-Vis spectroscopy, or by SDS capillary gel electrophoresis) and an antibody which has been purified to such an extent at least fifteen amino acids of the amino terminus or an internal amino acid sequence can be determined or purified to homogeneity, the homogeneity being determined by SDS-PAGE under reducing or non-reducing conditions (the detection can be determined by Coomassie blue staining or preferably by silver staining)
  • ei Antibodies are usually produced by one or more purification steps.
  • specific binding refers to an antibody or binder that binds to a predetermined antigen / target molecule.
  • Specific binding of an antibody or binder typically describes an antibody or binding with an affinity of at least 10 "7 M (as Kd value, so preferably those with smaller Kd values as IQ""7 M), wherein the antibody or binder has at least two-fold higher affinity for the predetermined antigen / target molecule than for a non-specific antigen / target molecule (eg, bovine serum albumin, or casein) that is not the predetermined antigen / target molecule or a closely related antigen / target molecule affinity of at least 10 -7 M (as Kd value, so preferably those with smaller Kd values than 10 ⁇ 7 M), preferably at least 10 " ⁇ M, particularly preferably in the range of 10" 9 M to 10 "1 1 m up.
  • the Kd values can be determined by, for example, surface plasmon resonance spectroscopy.
  • the antibody-drug conjugates of the invention also have affinities in these areas.
  • the conjugation of the active ingredients preferably does not significantly affect the affinity (as a rule, the affinity is reduced by less than an order of magnitude, eg, at most from 10 -8 M to 10 -7 M).
  • the antibodies used according to the invention are furthermore preferably characterized by a high selectivity.
  • a high selectivity is present when the antibody according to the invention has an affinity to the target protein which is better by at least a factor 2, preferably factor 5 or particularly preferred factor 10 than at an independent other antigen, eg human serum albumin (the affinity can be determined eg by surface plasmon resonance spectroscopy) ,
  • the antibodies used according to the invention are preferably cross-reactive.
  • the antibody used according to the invention binds not only the human target protein but also binds the species target protein in the species used for the studies .
  • the antibody used according to the invention is, in addition to the human target protein, cross-reactive to the target protein of at least one other species.
  • species of the family rodents, dogs and non-human primates are preferably used.
  • Preferred rodent species are mouse and rat.
  • Preferred non-human primates are rhesus monkeys, chimpanzees and long-tailed macaques.
  • the antibody used according to the invention is cross-reactive with the target protein of at least one other species selected from the group of species consisting of mouse, rat and long-tailed macaque (Macaca fascicularis).
  • the target protein of at least one other species selected from the group of species consisting of mouse, rat and long-tailed macaque (Macaca fascicularis).
  • antibodies used according to the invention which, in addition to the human target protein, are at least cross-reactive with the mouse target protein.
  • the target molecule to which the binder, eg, an antibody or an antigen-binding fragment thereof, is directed is a cancer target molecule.
  • the term "cancer target molecule” describes a target molecule that is more abundant on one or more types of cancer cells than non-cancerous cells of the same tissue type
  • the cancer targeting molecule is selectively present on one or more cancer cell types compared to non-cancerous cells of the same tissue type wherein selectively describes at least two-fold accumulation on cancer cells compared to non-cancer cells of the same tissue type (a "selective cancer target molecule").
  • selective cancer target molecule allows the selective therapy of cancer cells with the conjugates of the invention.
  • Antibodies that are specifically directed against an antigen may be made by those of ordinary skill in the art by methods known to those in the art (such as recombinant expression) or purchased commercially (such as from Merck KGaA, Germany). Examples of known commercially available antibodies in cancer therapy are Erbitux® (Cetuximab, Merck KGaA), Avastin® (Bevacizumab, Roche) and Herceptin® (Trastuzumab, Genentech).
  • the antibody is produced recombinantly in CHO cells. All of these antibodies can also be made as aglycosylated variants of these antibodies, either by deglycosylation by PNGase F or by mutation of N297 (Kabat numbering) of the heavy chain to any amino acid.
  • the target molecule is a selective cancer target molecule.
  • the target molecule is a protein.
  • the target molecule is an extracellular target molecule.
  • the extracellular target molecule is a protein.
  • Cancer target molecules are known to the person skilled in the art. Examples of this are listed below. Examples of cancer target molecules are:
  • EGF receptor NCBI reference sequence NP_005219.2
  • EGFR Receptor Precursor [Homo sapiens]
  • the extracellular domain is underlined.
  • Mesothelin is encoded by amino acids 296-598. Amino acids 37-286 encode "megakaryocyte-potentiating factor”. Mesothelin is anchored in the cell membrane by a GPI anchor and is localized extracellularly.
  • the extracellular domain is underlined.
  • CD52 NCBI reference sequence NP OO 1794.2
  • CD20 NCBI reference sequence NP 068769.2
  • lymphocyte activating antigen CD30 (SwissProt ID P28908), SEQ ID NO: 220
  • tumor necrosis factor receptor superfamily member 8 isoform 1 precursor [Homo sapiens] MRVLLAALGLLFLGALRAFPQDRPFEDTCHGNPSHYYDKAVRRCCYRCPMGLFPTQQCP

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