Prodrugs of cytotoxic active agents having enzymatically cleavable groups

Abstract

The invention relates to novel prodrugs or conjugates of the general formula (Ia) in which cytotoxic drugs, for example kinesin spindle protein inhibitors, are masked with legumain-cleavable groups and hence release the drug, and to the use of these prodrugs or conjugates for treatment and/or prevention of diseases, and to the use of these prodrugs or conjugates for production of medicaments for treatment and/or prevention of diseases, especially of hyperproliferative and/or angiogenic disorders, for example cancers.

1 - 44 . (canceled) 
     
     
         45 . An antibody-drug conjugate of Formula IIIa′ 
       
         
           
           
               
               
           
         
         or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein: 
         AB is an antibody or an antigen-binding antibody fragment, 
         L c  is a linker, 
         A 1  is a side-chain of one of the amino acids Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, citrulline, or His, 
         A 2  is a side-chain of one of the amino acids D-Ala, D-Pro, D-Val, D-Nva, D-Leu, D-Ile, D-Met, D-Phe, D-Tyr, D-Trp, D-Ser, D-Thr, D-Cys, D-Asn, D-Gln, D-Asp, D-Glu, D-Lys, D-Arg, D-citrulline, or D-His, 
         R 2a  is —H, C 1 -C 3 -alkyl, or R 2a  is the bond to the methylene group of the proline ring if A 2  is a side-chain of D-Pro, 
         X is —CONH 2  or —COOH, 
         L a  is a self-immolative linker, 
         D 1  is a cytotoxic drug, 
         m is 0, 1, or 2; 
         n is 0 or 1; 
         r is 0 or 1; and 
         s is 1 to 20. 
       
     
     
         46 . The antibody-drug conjugate of  claim 45 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein A 1  is a side-chain of one of the amino acids Ala or Val. 
     
     
         47 . The antibody-drug conjugate of  claim 45 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein A 2  is a side-chain of one of the amino acids D-Ala, D-Pro, D-Asp, D-Asn, D-His or D-Ser. 
     
     
         48 . The antibody-drug conjugate of  claim 45 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, where R 2a  is —H or —CH 3 . 
     
     
         49 . The antibody-drug conjugate of  claim 45 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, where m is 1. 
     
     
         50 . The antibody-drug conjugate of  claim 45 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein D 1  is a drug selected from mitomycin, doxorubicin, aminopterin, actinomycin, bleomycin, 9-aminocamptothecin, n8-acetylspermidine, 1-(2-chloroethyl)-1,2-dimethanesulphonyl hydrazide, tallysomycin, cytarabine, etoposide, camptothecin, taxol, esperamicin, podophyllotoxin, anguidine, vincristine, vinblastine, morpholine-doxorubicin, n-(5,5-diacetoxypentyl)doxorubicin, duocarmycin, auristatin, pyrrolobenzodiazepine derivatives, calicheamicin, daunorubicin, camptothecin, exatecan or a kinesin spindle protein inhibitor. 
     
     
         51 . The antibody-drug conjugate of  claim 45 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein D 1  is a cytotoxic drug of Formula (IIa): 
       
         
           
           
               
               
           
         
         wherein
 X 1  is N, 
 X 2  is N, and 
 X 3  is C; 
 
         or
 X 1  is N, 
 X 2  is C, and 
 X 3  is N; 
 
         or
 X 1  is CH or CF, 
 X 2  is C, and 
 X 3  is N; 
 
         or
 X 1  is NH, 
 X 2  is C, and 
 X 3  is C; 
 
         or
 X 1  is CH, 
 X 2  is N, and 
 X 3  is C; 
 
         A is —C(═O)—, —S(═O)—, —S(═O) 2 —, or —S(═O) 2 —NH, 
         R 1  is —H, -MOD or —(CH 2 ) 0-3 Z, 
         Z is —H, —NHY 3 , —OY 3 , —SY 3 , halogen, —C(═O)—NY 1 Y 2 , or —C(═O)—OY 3 , 
         Y 1  and Y 2  are independently —H, —NH 2 , —(CH 2 CH 2 O) 0-3 —(CH 2 ) 0-3 Z′ or —CH(CH 2 W)Z′, 
         Y 3  is —H or —(CH 2 ) 0-3 Z′, 
         Z′ is —H, —NH 2 , —S(═O) 3 H, —COOH, —NH—C(═O)—CH 2 —CH 2 —CH(NH 2 )C(═O)— or —(C(═O)—NH—CHY 4 ) 1-3 COOH, 
         W is —H or —OH, 
         Y 4  is linear or branched C 1-6  alkyl, optionally substituted by —NH—C(═O)—NH 2 , or is aryl or benzyl optionally substituted by —NH 2 , 
         R 2  is —H, -MOD, —C(═O)—CHY 4 —NHY 5  or —(CH 2 ) 0-3 Z, 
         Z is —H, halogen, —OY 3 , —SY 3 , —NHY 3 , —C(═O)—NY 1 Y 2 , or —C(═O)—OY 3 , 
         Y 1  and Y 2  are independently —H, —NH 2 , or —(CH 2 ) 0-3 Z′, 
         Y 3  is —H or —(CH 2 ) 0-3 Z′, 
         Z′ is —H, —S(═O) 3 H, —NH 2  or —COOH, 
         Y 4  is linear or branched C 1-6  alkyl- optionally substituted by —NHC(═O)—NH 2 , or is aryl or benzyl optionally substituted by —NH 2 , 
         Y 5  is —H or —C(═O)—CHY 6 —NH 2 , 
         Y 6  is linear or branched C 1-6 -alkyl, 
         R 3  is -MOD, or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group which may be substituted by one to three OH groups, one to three halogen atoms, one to three
 mono-, di- or trihalogenated alkyl groups, one to three —O-alkyl groups, one to three —SH groups, one to three —S-alkyl groups, one to three —O—C(═O)-alkyl groups, one to three —O—C(═O)—NH-alkyl groups, one to three —NH—C(═O)-alkyl groups, one to three —NH—C(═O)—NH-alkyl groups, one to three —S(═O) 0-2 -alkyl groups, one to three —S(═O) 2 —NH-alkyl groups, 1-3 —NH-alkyl groups, one to three —N(alkyl) 2  groups, one to three NH 2  groups or one to three —(CH 2 ) 0-3 Z groups, 
 
         Z is —H, halogen, —OY 3 , —SY 3 , —NHY 3 , —C(═O)—NY 1 Y 2  or —C(═O)—OY 3 , 
         Y 1  and Y 2  are independently —H, —NH 2 , or —(CH 2 ) 0-3 Z′, 
         Y 3  is —H, —(CH 2 ) 0-3 —CH(NHC(═O)CH 3 )Z′, —(CH 2 ) 0-3 —CH(NH 2 )Z′ or —(CH 2 ) 0-3 Z′, 
         Z′ is —H, —S(═O) 3 H, —NH 2  or —C(═O)—OH, 
         R 4  represents the bond to -[L a ] n - of Formula IIIa′; 
         R 5  is —H, —NH 2 , —NO 2 , halogen, —CN, CF 3 , —OCF 3 , —CHF 2 , —CH 2 F, —SH, or —(CH 2 ) 0-3 Z, 
         Z is —H, —OY 3 , —SY 3 , halogen, —NHY 3 , —C(═O)—NY 1 Y 2 , or —C(═O)—OY 3 , 
         Y 1  and Y 2  are independently —H, —NH 2 , or —(CH 2 ) 0-3 Z′, 
         Y 3  is —H or —(CH 2 ) 0-3 Z′, 
         Z′ is —H, —S(═O) 3 H, —NH 2  or —COOH, 
         R 6  and R 7  are independently —H, —CN, C 1-10 -alkyl, fluoro-C 1-10 -alkyl, C 2-10 -alkenyl, fluoro-C 2-10 -alkenyl, C 2-10 -alkynyl, fluoro-C 2-10 -alkynyl, hydroxyl, —NO 2 , —NH 2 , —COOH or halogen, 
         R 8  is C 1-10 -alkyl, fluoro-C 1-10 -alkyl, C 2-10 -alkenyl, fluoro-C 2-10 -alkenyl, C 2-10 -alkynyl, fluoro-C 2-10 -alkynyl, C 4-10 -cycloalkyl, fluoro-C 4-10 -cycloalkyl or —(CH 2 ) 0-2 —(HZ 2 ), 
         HZ 2  is a 4- to 7-membered heterocycle having up to two heteroatoms selected from N, O and S, which may be substituted by —OH, —COOH, or —NH 2 ; 
         R 9  is —H, —F, —CH 3 , —CF 3 , —CH 2 F or —CHF 2 , 
         -MOD is —(NR 10 ) n -(G1) o -G2-G3, 
         R 10  is —H or C 1 -C 3 -alkyl, 
         G1 is —NH—C(═O)—, —C(═O)—NH—, or 
       
       
         
           
           
               
               
           
         
         n is 0 or 1; 
         o is 0 or 1, and 
         G2 is a straight-chain or branched hydrocarbon chain which has 1 to 20 carbon atoms and may be interrupted once or more than once by —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR y —, —NR y C(═O)—, —C(═O)NR y —, —NR y NR y —, —S(═O) 2 —NR y NR y —, —C(═O)—NR y NR y —, —C(═O)—, or —CR x ═N—O—, and
 wherein the straight-chain or branched hydrocarbon chain may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , sulphonamide, sulphone, sulphoxide, or sulphonic acid, 
 
         R y  is —H, phenyl, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl or C 2 -C 10 -alkynyl, each of which may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , sulphonamide, sulphone, sulphoxide, or sulphonic acid, 
         R x  is —H, C 1 -C 3 -alkyl, or phenyl, 
         G3 is —H or —COOH, and 
         -MOD has at least one —COOH group, 
         or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof. 
       
     
     
         52 . The antibody-drug conjugate of  claim 51 , or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof, wherein X 1  is CH, X 2  is C, and X 3  is N. 
     
     
         53 . The antibody-drug conjugate of  claim 51 , or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof, wherein R 6  and R 7  are independently —H, C 1-3 -alkyl or halogen. 
     
     
         54 . The antibody-drug conjugate of  claim 51 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein R 8  is C 1-4 -alkyl or cyclohexyl. 
     
     
         55 . The antibody-drug conjugate of  claim 45 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein D 1  is a cytotoxic drug of Formula (IIc): 
       
         
           
           
               
               
           
         
         wherein 
         A is —C(═O)—, 
         R 1  is —H, -MOD or —(CH 2 ) 0-3 Z, 
         Z is —H, —NHY 3 , —OY 3 , —SY 3 , halogen, —C(═O)—NY 1 Y 2 , or —C(═O)—OY 3 , 
         Y 1  and Y 2  are independently —H, —NH 2 , —(CH 2 CH 2 O) 0-3 —(CH 2 ) 0-3 Z′ or —CH(CH 2 W)Z′, 
         Y 3  is —H or —(CH 2 ) 0-3 Z′, 
         Z′ is —H, —NH 2 , —S(═O) 3 H, —COOH, —NH—C(═O)—CH 2 —CH 2 —CH(NH 2 )C(═O)— or —(C(═O)—NH—CHY 4 ) 1-3 COOH, 
         W is —H or —OH, 
         Y 4  is linear or branched C 1-6  alkyl, optionally substituted by —NH—C(═O)—NH 2 , or is aryl or benzyl optionally substituted by —NH 2 , 
         R 3  is —CH 2 OH, —CH 2 OCH 3 , —CH(CH 3 )OH or —CH(CH 3 )OCH 3 ; 
         R 4  represents the bond to -[L a ] n - of Formula IIIa′; 
         R 8  is C 1-4 -alkyl or cyclohexyl, and 
         -MOD is —C(O)—NH—CH 2 —CH 2 —CO—NH—(CHX) 2-6 —COOH, or —C(O)—NH—CH 2 —CH 2 —NH—CO—(CHX) 2-6 —COOH;
 wherein X is —H, —NH 2  or —COOH. 
 
       
     
     
         56 . The antibody-drug conjugate of  claim 55 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein
 R 1  is -MOD; and   -MOD is —C(O)—NH—CH 2 —CH 2 —CO—NH—CH(COOH)—CH 2 —CH 2 —COOH, —C(O)—NH—CH 2 —CH 2 —NH—CO—CH 2 —CH 2 —CH(NH 2 )—COOH, or —C(O)—NH—CH 2 —CH 2 —CO—NH—(CH 2 ) 4 —COOH.   
     
     
         57 . The antibody-drug conjugate of  claim 45 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein L c  is bound to a cysteine side chain or a cysteine residue of the antibody or antigen binding fragment thereof, and has the formula:
   —(C═O) m -L1-L2-§ §
   wherein   m is 0 or 1;   § § is the bond to AB,   -L2- is the group   
       
         
           
           
               
               
           
         
         
           wherein 
           # 1  denotes the linkage site to the sulfur atom of the antibody or antigen binding fragment thereof, 
           # 2  denotes the linkage site to the L1 group, 
           L1 is —(NR 10 ) n -(G1) o -G2-, 
           R 10  is —H or C 1 -C 3 -alkyl, 
           G1 is —NHC(═O)— or 
         
       
       
         
           
           
               
               
           
         
         
           n is 0 or 1, 
           o is 0 or 1, and 
           G2 is a straight-chain or branched hydrocarbon chain having 1 to 100 carbon atoms, composed of arylene groups and/or straight-chain and/or branched and/or cyclic alkylene groups, which may be interrupted once or more than once, by one or more of the groups —O—, —S—, —S(═O)—, —S(═O) 2 , —NH—, —C(═O)—, —NMe-, —NHNH—, —S(═O) 2 —NHNH—, —NH—C(═O)—, —C(═O)—NH—, —C(═O)—NHNH— and a 5- to 10-membered aromatic or nonaromatic heterocycle having up to 4 heteroatoms selected from N, O, and S, —S(═O)— or —S(═O) 2 —, and
 wherein the side chains, if present, may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , NH—CNNH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid, 
 or one of the following groups: 
 
         
       
       
         
           
           
               
               
           
         
         wherein 
         Rx is —H, C 1 -C 3 -alkyl or phenyl. 
       
     
     
         58 . The antibody-drug conjugate of  claim 57 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein L c  has formula: 
       
         
           
           
               
               
           
         
         wherein 
         #3 is the bond to the cytotoxic drug, 
         #4 is the bond to the antibody or antigen binding fragment thereof, 
         w is 0 to 20; 
         x is 0 to 5; 
         y is 0 or 1; 
         z is 0 to 5; and 
         X 4  is —O—, —C(═O)—NH—, —NH—C(═O)— or 
       
       
         
           
           
               
               
           
         
       
     
     
         59 . The antibody-drug conjugate of  claim 45 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, having one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein: 
         AK 1  represents AB, wherein AB is bonded via a cysteine residue, 
         AK 2  represents AB, wherein AB is bonded via a lysine residue, 
         AK 3  represents AB, wherein AB is bonded via a glutamine residue, and 
         n is a number from 1 to 50. 
       
     
     
         60 . The antibody-drug conjugate of  claim 45 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein the antibody or the antigen-binding antibody fragment binds to an extracellular cancer target molecule. 
     
     
         61 . The antibody-drug conjugate of  claim 45 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein the antibody or the antigen-binding antibody fragment, binds to an extracellular cancer target molecule, and after the binding to the extracellular target molecule, is internalized by the cell. 
     
     
         62 . The antibody-drug conjugate of  claim 45 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein the antibody or antigen binding fragment thereof is an anti-HER2 antibody, an anti-EGFR antibody, an anti-B7H3 antibody, an anti-TWEAKR antibody, or an antigen-binding antibody fragment thereof. 
     
     
         63 . The antibody-drug conjugate of  claim 62 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein the antibody or antigen binding fragment thereof:
 (i) is an anti-EGFR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 2, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 3 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 4, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 6, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 7 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 8,   (ii) is an anti-HER2 antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 12, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 13 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 14, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 16, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 17 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 18,   (iii) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 22, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 23 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 24, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 26, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 27 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 28,   (iv) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 32, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 33 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 34, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 36, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 37 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 38,   (v) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 42, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 43 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 44, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 46, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 47 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 48,   (vi) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 52, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 53 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 54, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 56, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 57 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 58,   (vii) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 62, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 63 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 64, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 66, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 67 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 68,   (viii) is an anti-HER2 antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 72, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 73 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 74, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 76, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 77 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 78,   (ix) is an anti-HER2 antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 82, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 83 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 84, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 86, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 87 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 88,   (x) is an anti-B7H3 antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 92, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 93 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 94, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 96, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 97 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 98,   (xi) is an anti-B7H3 antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 102, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 103 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 104, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 106, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 107 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 108,   (xii) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 112, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 113 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 114, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 116, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 117 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 118,   (xiii) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 122, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 123 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 124, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 126, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 127 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 128,   (xiv) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 132, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 133 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 134, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 136, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 137 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 138,   (xv) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 142, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 143 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 144, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 146, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 147 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 148, or   (xvi) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) comprising the variable CDR1 sequence of the heavy chain (H-CDR1), as shown by SEQ ID NO: 152, the variable CDR2 sequence of the heavy chain (H-CDR2), as shown by SEQ ID NO: 153 and the variable CDR3 sequence of the heavy chain (H-CDR3), as shown by SEQ ID NO: 154, and a variable region of the light chain (VL) comprising the variable CDR1 sequence of the light chain (L-CDR1), as shown by SEQ ID NO: 156, the variable CDR2 sequence of the light chain (L-CDR2), as shown by SEQ ID NO: 157 and the variable CDR3 sequence of the light chain (L-CDR3), as shown by SEQ ID NO: 158, or is an antigen-binding fragment of these antibodies.   
     
     
         64 . The antibody-drug conjugate of  claim 62 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein the antibody or antigen binding fragment thereof:
 (i) is an anti-EGFR antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 1 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 5,   (ii) is an anti-HER2 antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 11 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 15,   (iii) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 21 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 25,   (iv) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 31 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 35,   (v) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 41 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 45,   (vi) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 51 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 55,   (vii) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 61 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 65,   (viii) is an anti-HER2 antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 71 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 75,   (ix) is an anti-HER2 antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 81 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 85,   (x) is an anti-B7H3 antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 91 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 95,   (xi) is an anti-B7H3 antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 101 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 105,   (xii) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 111 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 115,   (xiii) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 121 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 125,   (xiv) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 131 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 135,   (xv) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 141 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 145, or   (xvi) is an anti-TWEAKR antibody comprising a variable region of the heavy chain (VH) corresponding to SEQ ID NO: 151 and a variable region of the light chain (VL) corresponding to SEQ ID NO: 155,   or is an antigen-binding fragment of these antibodies.   
     
     
         65 . The antibody-drug conjugate of  claim 62 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, wherein the antibody or antigen binding fragment thereof:
 (i) is an anti-EGFR antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 9 and a region of the light chain corresponding to SEQ ID NO: 10,   (ii) is an anti-HER2 antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 19 and a region of the light chain corresponding to SEQ ID NO: 20,   (iii) is an anti-TWEAKR antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 29 and a region of the light chain corresponding to SEQ ID NO: 30,   (iv) is an anti-TWEAKR antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 39 and a region of the light chain corresponding to SEQ ID NO: 40,   (v) is an anti-TWEAKR antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 49 and a region of the light chain corresponding to SEQ ID NO: 50,   (vi) is an anti-TWEAKR antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 59 and a region of the light chain corresponding to SEQ ID NO: 60,   (vii) is an anti-TWEAKR antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 69 and a region of the light chain corresponding to SEQ ID NO: 70,   (viii) is an anti-HER2 antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 79 and a region of the light chain corresponding to SEQ ID NO: 80,   (ix) is an anti-HER2 antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 89 and a region of the light chain corresponding to SEQ ID NO: 90,   (x) is an anti-B7H3 antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 99 and a region of the light chain corresponding to SEQ ID NO: 100,   (xi) is an anti-B7H3 antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 109 and a region of the light chain corresponding to SEQ ID NO: 110,   (xii) is an anti-TWEAKR antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 119 and a region of the light chain corresponding to SEQ ID NO: 120,   (xiii) is an anti-TWEAKR antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 129 and a region of the light chain corresponding to SEQ ID NO: 130,   (xiv) is an anti-TWEAKR antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 139 and a region of the light chain corresponding to SEQ ID NO: 140,   (xv) is an anti-TWEAKR antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 149 and a region of the light chain corresponding to SEQ ID NO: 150, or   (xvi) is an anti-TWEAKR antibody comprising a region of the heavy chain corresponding to SEQ ID NO: 159 and a region of the light chain corresponding to SEQ ID NO: 160,   or is an antigen-binding fragment of these antibodies.   
     
     
         66 . A pharmaceutical composition, comprising an antibody-drug conjugate of  claim 45 , or a pharmaceutically salt, solvate, or salt of a solvate thereof, in combination with an inert non-toxic pharmaceutically suitable excipient. 
     
     
         67 . A method for treatment of a hyperproliferative disorder or angiogenic disorder in a patient in need thereof, comprising administering an effective amount of an antibody-drug conjugate according to  claim 45 .