Antibody drug conjugates (ADCS) and antibody prodrug conjugates (APDCS) with enzymatically cleavable groups
The present invention relates to novel binder-prodrug conjugates (APDCs) where binders are conjugated with inactive precursor compounds of kinesin spindle protein inhibitors, and to antibody-drug conjugates ADCs and to processes for producing these APDCs and ADCs.
1. A conjugate of an antibody or antigen-binding fragment thereof with one or more drug molecules or one or more prodrugs thereof, of the following formula:
BINDER L-KSP] n
wherein
BINDER is the antibody or antigen-binding fragment thereof,
L is a linker, wherein -L- is attached to a cysteine side chain of the antibody or antigen-binding fragment thereof,
n is a number from 1 to 50, and
KSP is a kinesin spindle inhibitor or prodrug thereof, wherein -L-KSP has the following formula (IIa):
wherein
X 1 is N, X 2 is N and X 3 is C; 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;
R 1 is —H, -L-#1, -MOD or —(CH 2 ) 0-3 Z,
wherein Z is —H, —NHY 3 , —OY 3 , —SY 3 , halogen, —C(═O)—NY 1 Y 2 or —CO—OY 3 ,
wherein Y 1 and Y 2 are independently —H, —NH 2 , —(CH 2 CH2O) 0-3 —(CH 2 ) 0-3 Z′ or —CH(CH 2 W)Z′,
wherein Y 3 is —H or —(CH 2 ) 0-3 Z′,
wherein Z′ is —H, NH 2 , SO 3 H, —COOH, —NH—C(═O)—CH 2 —CH 2 —CH(NH 2 )COOH or —(C(═O)—NH—CHY 4 ) 1-3 COOH,
wherein W is —H or —OH,
wherein Y 4 is straight-chain or branched C 1-6 -alkyl which is optionally substituted by —NH—C(═O)—NH 2 , or is aryl or benzyl which are optionally substituted by —NH 2 ;
R 2 is -L-#1, —H, -MOD, —C(═O)—CHY 4 —NHY 5 or —(CH 2 ) 0-3 Z, wherein Z is —H, halogen, —OY 3 , —SY 3 , —NHY 3 , —C(═O)—NY 1 Y 2 or —C(═O)—OY 3 ,
wherein Y 1 and Y 2 are independently —H, —NH 2 or —(CH 2 ) 0-3 Z′,
wherein Y 3 is —H or —(CH 2 ) 0-3 Z′,
wherein Z′ is —H, —SO 3 H, —NH 2 or —COOH;
wherein Y 4 is straight-chain or branched C 1-6 -alkyl which is optionally substituted by —NH—C(═O)—NH 2 , or is aryl or benzyl which are optionally substituted by —NH 2 ,
wherein Y 5 is —H or —C(═O)—CHY 6 —NH 2 ,
wherein Y 6 is straight-chain or branched C 1-6 -alkyl;
R 4 is -L-#1, —H, —C(═O)—CHY 4 —NHY 5 or —(CH 2 ) 0-3 Z,
wherein Z is —H, halogen, —OY 3 , —SY 3 , —NHY 3 , —C(═O)—NY 1 Y 2 or —C(═O)—OY 3 ,
wherein Y 1 and Y 2 are independently —H, —NH 2 or —(CH 2 ) 0-3 Z′,
wherein Y 3 is —H or —(CH 2 ) 0-3 Z′,
wherein Z′ is —H, —SO 3 H, —NH 2 or —COOH;
wherein Y 4 is straight-chain or branched C 1-6 -alkyl which is optionally substituted by —NH—C(═O)—NH 2 , or is aryl or benzyl which are optionally substituted by —NH 2 ,
wherein Y 5 is —H or —C(═O)—CHY 6 —NH 2 ,
wherein Y 6 is straight-chain or branched C 1-6 -alkyl;
or
R 4 is a group of the formula
R 21 —(C(═O)) (0-1) —(P3) (0-2) —P2—NH—CH(CH 2 C(═O)—NH 2 )—C(═O)— or
R 21 —(C(═O)) (0-1) —(P3) (0-2) -P2—NH—CH(CH 2 COOH)—C(═O)—,
wherein R 21 is a C 1-10 -alkyl, C 5 -aryl or C 6-10 -aralkyl, C 5-10 -heteroalkyl, C 1-10 -alkyl-O—C 6-10 -aryl, C 5-10 -heterocycloalkyl, heteroaryl, heteroarylalkyl, 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 5-10 -heterocycloalkoxy group which may be mono- or polysubstituted by — NH 2 , —NH-alkyl, —N(alkyl) 2 , NH—C(═O)-alkyl, —N(alkyl)-C(═O)-alkyl, —SO 3 H, —S(═O) 2 NH 2 , —S(═O) 2 —N(alkyl) 2 , —COOH, —C(═O)NH 2 , —C(═O)N(alkyl) 2 , or —OH, —H or an -Ox-(CH 2 CH 2 O) y —R 22 group,
wherein x is 0 or 1
wherein v is a number from 1 to 20, and
wherein R 22 is —H, -alkyl, —CH 2 —COOH, —CH 2 —CH 2 —COOH, or —CH 2 —CH 2 —NH 2 ),
wherein P2 is an amino acid selected from the group consisting of Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, citrulline and His or the respective N-alkyl amino acids;
wherein P3 is an amino acid selected from the group consisting of Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, citrulline and His or the respective N-alkyl amino acids;
or
R 2 and R 4 together represent (forming a pyrrolidine ring) —CH 2 —CHR 10 — or #-CHR 10 —CH 2 —,
wherein R 10 is —H, —NH 2 , —SO 3 H, —COOH, —SH, halogen (especially F or Cl), C 1-4 -alkyl, C 1-4 -haloalkyl, C 1-4 -alkoxy, hydroxyl-substituted C 1-4 -alkyl, COO(C 1-4 -alkyl), —OH or R 21 —C(═O)—P3-P2—NH—CH(CH 2 C(═O)—NH 2 )—C(═O)—SIG-,
wherein SIG is a self-immolative group which, after cleavage of the C(═O)—SIG bond, releases the secondary amine;
A is —C(═O)—, —S(═O)—, —S(═O) 2 —, —S(═O) 2 NH— or —C(═N—NH 2 )—;
R 3 is -L-#1, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, which may in each case be 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—C(═O)-alkyl groups, 1-3 —O—C(═O)—NH-alkyl groups, 1-3 —NH—C(═O)-alkyl groups, 1-3 —NH—C(═O)—NH-alkyl groups, 1-3 —S(O) n -alkyl groups, 1-3 —S(═O) 2 —NH-alkyl groups, 1-3 —NH-alkyl groups, 1-3 —N(alkyl) 2 groups, 1-3 —NH 2 groups or 1-3 —(CH 2 ) 0-3 Z groups,
wherein Z is —H, halogen, —OY 3 , —SY 3 , —NHY 3 , —C(═O)—NY 1 Y 2 or —C(═O)—OY 3 ,
wherein n is 0, 1 or 2,
wherein Y 1 and Y 2 are independently —H, —NH 2 or —(CH 2 ) 0-3 Z′,
wherein Y 3 is —H, —(CH 2 ) 0-3 —CH(NHCOCH 3 )Z′, —(CH 2 ) 0-3 —CH(NH 2 )Z′ or —(CH 2 ) 0-3 Z′,
wherein Z′ is —H, —SO 3 H, —NH 2 or —COOH;
R 5 is —H, —NH 2 , —NO 2 , halogen, —CN, —CF 3 , —OCF 3 , —CH 2 F, —CH 2 F, —SH or —(CH 2 ) 0-3 Z,
wherein Z is —H, —OY 3 , —SY 3 , halogen, —NHY 3 , —C(═O)—NY 1 Y 2 or —C(═O)—OY 3 ,
wherein Y 1 and Y 2 are independently —H, —NH 2 or —(CH 2 ) 0-3 Z′,
wherein Y 3 is —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, 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, hydroxy, —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 ),
wherein HZ 2 is a 4- to 7-membered heterocycle having up to two heteroatoms selected from the group consisting of N, O and S, wherein each of these groups may be substituted by —OH, —COOH or —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 is or (in the case of R′) contains -L-#1, -L is the linker and #1 is the bond to the antibody or antigen-binding fragment thereof,
wherein -MOD is —(NR 10 ) n -(G1) o -G2-G3,
wherein R 10 is —H or C 1 -C 3 -alkyl;
wherein G1 is —NH—C(═O)—, —C(═O)NH— or
n is 0 or 1;
o is 0 or 1;
and
wherein G2 is a straight-chain and/or branched hydrocarbon group which has 1 to 10 carbon atoms and which may be interrupted once or more than once by one or more of the groups —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—,
wherein 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 , —NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid
wherein Rx is —H, C 1 -C 3 -alkyl or phenyl,
wherein the hydrocarbon chain including a C 1 -C 10 -alkyl group optionally substituted on the hydrocarbon group as side chain, if present, may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , —NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid,
wherein G3 is —H or —COOH;
wherein -MOD has at least one —COOH group,
wherein the conjugate comprises a legumain cleavable group —(C═O) (0-1) —(P3) (0-2) -P2—NH—CH(CH 2 C(═O)—X)—C(═O)—,
wherein X is —NH 2 or —COOH;
wherein P2 is an amino acid selected from the group consisting of Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, citrulline and His or the respective N-alkyl amino acids;
wherein P3 is an amino acid selected from the group consisting of Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, citrulline and His or the respective N-alkyl amino acids;
or a salt, a solvate, a salt of the solvate, or an epimer thereof.
2. The conjugate according to claim 1 , wherein R 4 is the group of the formula R 21 —(C(═O)) (0-1) —(P3) (0-2) -P2—NH—CH(CH 2 C(═O)NH 2 )—C(═O)—.
3. The conjugate according to claim 1 , wherein P2 is selected from the group consisting of Ala, Gly, Val, Leu, Ile, Pro, Ser, Thr and Asn, or the respective N-alkyl amino acids.
4. The conjugate according to claim 1 , wherein P3 is selected from the group consisting of Pro, Ala, Val, Leu, Ile, Gly, Ser and Gln, or the respective N-alkyl amino acids.
5. The conjugate according to claim 1 , wherein P2 is Ala.
6. The conjugate according to claim 1 , wherein P3 is Ala.
7. The conjugate according to claim 1 , wherein
R 21 is —H, a C 1-5 -alkyl-, C 5-10 -aralkyl-, C 1-5 -alkoxy-, C 6-10 -aryloxy group, C 5-10 -heteroalkyl, C 5-10 -heterocycloalkyl, heteroaryl, heteroarylalkyl, C 5-10 -heteroalkoxy or a C 5-10 -heterocycloalkoxy group, each of which may be substituted by —COOH, —C(═O)—Oalkyl, —C(═O)O—NH 2 , —NH 2 or —N(alkyl) 2 , or a —O x —(CH 2 CH 2 O) y —R 22 group,
wherein x is 0 or 1,
wherein v is a number from 1 to 20, and
R 22 is —H, -alkyl, —CH 2 —COOH, —CH 2 —CH 2 —COOH, or —CH 2 —CH 2 —NH 2 ).
8. The conjugate according to claim 1 , wherein
R 4 is -L-#1 and comprises the group of the formula
—(C═O) (0-1) —(P3) (0-2) -P2—NH—CH(CH 2 C(═O)—NH 2 )—C(═O)—,
wherein P2 is an amino acid selected from the group consisting of Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, citrulline and His or the respective N-alkyl amino acids; and
wherein P3 is an amino acid selected from the group consisting of Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, citrulline and His or the respective N-alkyl amino acids.
9. The conjugate according to claim 1 , wherein the conjugate is an antibody-prodrug conjugate, wherein
R 4 is the group of the formula
R 21 —(C═O) (0-1) —(P3) (0-2) -P2—NH—CH(CH 2 C(═O)—NH 2 )—C(═O)—,
wherein R 21 is a C 1-10 -alkyl, C 5-10 -aryl or C 6-10 -aralkyl, C 5-10 -heteroalkyl, C 1-10 -alkyl-O—C 6-10 -aryl, C 5-10 -heterocycloalkyl, heteroaryl, heteroarylalkyl, 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 5-10 -heterocycloalkoxy group which may be mono- or polysubstituted by —NH 2 , —NH-alkyl, —N(alkyl) 2 , —NH—C(═O)-alkyl, —N(alkyl)-C(═O)-alkyl, —SO 3 H, —S(═O) 2 —NH 2 , —S(═O) 2 —N(alkyl) 2 , —COOH, —C(═O)—NH 2 , —C(═O)—N(alkyl) 2 or —OH, or —H or a —O x —(CH 2 CH 2 O)v-R 22 group,
wherein x is 0 or 1;
wherein v is a number from 1 to 20, and
wherein R 22 is —H, -alkyl, —CH 2 —COOH, —CH 2 —CH 2 —COOH, or —CH 2 —CH 2 —NH 2 ,
wherein P2 is an amino acid selected from the group consisting of Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, citrulline and His or the respective N-alkyl amino acids; and
wherein each P3 is an amino acid independently selected from the group consisting of Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, citrulline and His or the respective N-alkyl amino acids.
10. The conjugate according to claim 1 wherein R 1 or R 3 is -L-#1.
11. The conjugate according to claim 1 , wherein X 1 is CH, X 2 is C and X 3 is N.
12. The conjugate according to claim 1 , wherein R 6 and R 7 are independently —H, C 1-3 -alkyl or halogen.
13. The conjugate according to claim 12 , wherein R 6 and R 7 are —F.
14. The conjugate according to claim 1 , wherein R 8 is C 1-4 -alkyl or cyclohexyl.
15. The conjugate according to claim 1 , wherein R 9 is H.
16. The conjugate according to claim 1 , wherein the antibody or antigen-binding fragment thereof an antibody.
17. The conjugate according to claim 16 , wherein each drug molecule is attached to different amino acids of the antibody via the linker.
18. The conjugate according to claim 1 , wherein the conjugate has on average 1.2 to 20 drug molecules or prodrugs per antibody or antigen-binding fragment thereof.
19. The conjugate according to claim 1 , wherein the antibody or antigen-binding fragment thereof binds to a cancer target molecule.
20. The conjugate according to claim 19 , wherein the antibody or antigen-binding fragment thereof binds to an extracellular target molecule.
21. The conjugate according to claim 20 , wherein the antibody or antigen-binding fragment thereof, after binding to the extracellular target molecule, is internalized and processed intracellularly by the cell expressing the target molecule.
22. The conjugate according to claim 16 , wherein the antibody or antigen-binding fragment thereof is a human, humanized or chimeric monoclonal antibody or an antigen-binding fragment thereof.
23. The conjugate according to claim 22 , wherein the antibody or antigen-binding fragment thereof is an anti-HER2 antibody, an anti-EGFR antibody, an anti-TWEAKR antibody or an antigen-binding fragment thereof.
24. The conjugate according to claim 23 , wherein the anti-TWEAKR antibody binds specifically to amino acid D in position 47 (D47) of TWEAKR (SEQ ID NO:169).
25. The conjugate according to claim 23 , wherein the anti-TWEAKR antibody is the anti-TWEAKR antibody TPP-2658.
26. The conjugate according to claim 23 , wherein the antibody or antigen-binding fragment thereof is an anti-EGFR antibody and R 3 is -L-#1.
27. The conjugate according to claim 1 , wherein the linker -L- has one of the basic structures (i) to (iv) below:
(i) —(C═O) m -SG1-L1-L2-
(ii) —(C═O) m -L1-SG-L1-L2-
(iii) —(C═O) m -L1-L2-
(iv) —(C═O) m -L1-SG-L2-
wherein m is 0 or 1, SG and SG1 are in vivo cleavable groups, each L1 is independently organic groups not cleavable in vivo, and L2 is a coupling group to the antibody or antigen-binding fragment thereof.
28. The conjugate according to claim 27 , wherein the in vivo cleavable group SG is a 2-8 oligopeptide group, or a disulphide, a hydrazone, an acetal or an aminal and SG1 is a 2-8 oligopeptide group.
29. The conjugate according to claim 1 , wherein
the linker is attached to the cysteine side chain and has the following formula:
§ —(C═O) m -L1-L2-§§
wherein
m is 0 or 1;
§ represents the bond to the drug molecule and §§ represents the bond to the antibody or antigen-binding fragment thereof, and -L2- is
wherein
# 1 denotes the point of attachment to the sulphur atom of the antibody or antigen-binding fragment thereof,
#2 denotes the point of attachment to the group L1,
L1 is —(NR 10 ) n -(G1)o-G2-, wherein
R 10 is —H, —NH 2 or C 1 -C 3 -alkyl;
G1 is —NH—C(═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 from arylene groups and/or straight-chain and/or branched and/or cyclic alkylene groups and which may be interrupted once or more than once by one or more of the groups —O—, —S—, —SO—, —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 non-aromatic heterocycle having up to 4 heteroatoms selected from the group consisting of N, O and S, —S(═O)— or —S(═O) 2 —, wherein the side chains, if present, may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , —NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid, or
is one of the following groups:
wherein Rx is —H, —C 1 -C 3 -alkyl or phenyl.
30. The conjugate according to claim 29 , wherein L2 is represented by one or both of the formulae below:
wherein
# 1 denotes the point of attachment to the sulphur atom of the antibody or antigen-binding fragment thereof,
#2 denotes the point of attachment to group L 1 ,
R 22 is —COOH, and the bonds to the sulphur atom of the antibody or antigen-binding fragment thereof are present in one of these two structures to an extent of more than 80% (based on the total number of bonds in the linker to the antibody or antigen-binding fragment thereof).
31. The conjugate according to claim 29 , wherein L 1 has the following formulae:
wherein r is a number from 0 to 8.
32. The conjugate according to claim 29 , wherein the hydrocarbon chain is interrupted by one group selected from the group consisting of:
wherein X is —H or a C 1-10 -alkyl group which may optionally be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , —NH—CN—NH 2 , sulphone, sulphoxide or sulphonic acid.
33. The conjugate according to claim 6 , wherein the linker has the formula below:
wherein
#3 represents the bond to the drug molecule,
#4 represents the bond to the antibody or antigen-binding fragment thereof,
R 11 is —NH 2 ;
B is —[(CH 2 ) x —(X 4 ) y ]W—(CH 2 ) z —,
w is 0 to 20;
x is 0 to 5;
is 0 or 1;
z is 0 to 5; and
X 4 is —O—, —C(═O)—NH— or —NH—C(═O)—
34. The conjugate according to claim 25 , wherein the conjugate satisfies one of the following formulae:
wherein
X1 is N, X2 is N and X3 is C; or
X1 is CH or CF, X2 is C and X3 is N; or
X1 is NH, X2 is C and X3 is C; or
X1 is CH, X2 is N and X3 is C;
AK 1 is an antibody or antigen-binding fragment thereof bound via a sulphur atom of the antibody or antigen-binding fragment thereof,
n is a number from 1 to 20; and
L 1 is an optionally branched hydrocarbyl group which has 1 to 70 carbon atoms, or is a straight-chain or branched hydrocarbyl 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 singly or multiply interrupted by one or more of the groups —O—, —S—, —SO—, —SO 2 —, —NH—, —C(═O)—, —C(═O)—NH—, —NH—C(═O)—, —NMe-, —NHNH—, —S(═O) 2 —, —NHNH—, —C(═O)—NHNH— and a 5- to 10-membered aromatic or nonaromatic heterocycle having up to 4 heteroatoms selected from the group consisting of N, O and S, —S(═O)— or —S(═O) 2 —, wherein the side chains, if present, may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , —NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid, and
SG1 is a 2-8 oligopeptide;
L4 is a single bond or a group —(C═O) y -G4-,
wherein y is 0 or 1, and
wherein G4 is a straight-chain or branched hydrocarbyl 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 singly or multiply interrupted by one or more of the groups —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —C(═O)—, —NH—C(═O)—, —C(═O)NH—, —Nme-, —NHNH—, —S(═O) 2 —NHNH—, —C(═O)—NHNH— and a 5- to 10-membered aromatic or nonaromatic heterocycle having up to 4 heteroatoms selected from the group consisting of N, O and S, —S(═O)— or —S(═O) 2 —,
wherein the side chains, if present, may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , —NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid;
wherein the hydrogen atom in position R 4 of formula IIa (i.e. in the —NH 2 group) is replaced by legumain-cleavable group of the formula
R 21 —(C═O) (0-1) —(P3) (0-2) -P2—NH—CH(CH 2 C(═O)—NH 2 )—C(═O)—,
wherein
R 21 is a C 1-10 -alkyl, C 5-10 -aryl or C 6-10 -aralkyl, C 5-10 -heteroalkyl, C 1-10 -alkyl-O—C 6-10 -aryl, C 5-10 -heterocycloalkyl, heteroaryl, heteroarylalkyl, 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 5-10 -heterocycloalkoxy group which may be mono- or polysubstituted by —NH 2 , —NH-alkyl, —N(alkyl) 2 , —NH—C(═O)-alkyl, —N(alkyl)-C(═O)-alkyl, —SO 3 H, —S(═O) 2 NH 2 , —S(═O) 2 —N(alkyl) 2 , —COOH, —C(═O)—NH 2 , —C(═O)—N(alkyl) 2 , or —OH, —H or an —O x —(CH 2 CH 2 O) v —R 22 group,
wherein x is 0 or 1,
wherein v is a number from 1 to 20, and
R 22 is —H, -alkyl, —CH 2 —COOH, —CH 2 —CH 2 —COOH, or —CH 2 —CH 2 —NH 2 ;
P2 is an amino acid selected from the group consisting of Gly, Pro, Ala, Val, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg and His or one of the respective N-alkyl amino acids;
P3 is an amino acid selected from the group consisting of Gly, Pro, Ala, Val, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg and His or one of the respective N-alkyl amino acids.
35. A conjugate of an antibody or antigen-binding fragment thereof with one or more drug molecules wherein the conjugate has one or both of the following formulae:
wherein
AK 1 or AK 1A is an antibody or antigen-binding fragment thereof bound via a sulphur atom of the antibody or antigen-binding fragment thereof,
n is a number from 1 to 20; and
L 1 is a straight-chain or branched hydrocarbyl 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 singly or multiply interrupted by one or more of the groups —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —C(═O)—, —C(═O)—NH—, —NH—C(═O)—, —NMe-, —NHNH—, —S(═O) 2 —NHNH—, —C(═O)—NHNH— and a 5- to 10-membered aromatic or nonaromatic heterocycle having up to 4 heteroatoms selected from the group consisting of N, O and S, —S(═O)— or —S(═O) 2 —, wherein the side chains, if present, may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , —NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid,
wherein the hydrogen atom in position R 4 of formula IIa (i.e. in the —NH 2 group) is replaced by a legumain-cleavable group of the formula
R 21 —(C═O) (0-1) —(P3) (0-2) -P2—NH—CH(CH 2 —C(═O)—NH 2 )—C(═O)—,
wherein
R 21 is a C 1-10 -alkyl, C 5-10 -aryl or C 6-10 -aralkyl, C 5-10 -heteroalkyl, C 1-10 -alkyl-O—C 6-10 -aryl, C 5-10 -heterocycloalkyl, heteroaryl, heteroarylalkyl, 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 5-10 -heterocycloalkoxy group which may be mono- or polysubstituted by —NH 2 , —NH-alkyl, —N(alkyl) 2 , —NH—C(═O)-alkyl, —N(alkyl)-C(═O)-alkyl, —SO 3 H, —S(═O) 2 —NH 2 , —S(═O) 2 —N(alkyl) 2 , —COOH, —C(═O)—NH 2 , —C(═O)—N(alkyl) 2 , or —OH, —H or an —O x —(CH 2 CH 2 O) v —R 22 group,
wherein x is 0 or 1,
wherein v is a number from 1 to 20, and
R 22 is —H, -alkyl, —CH 2 —COOH, —CH 2 —CH 2 —COOH or —CH 2 —CH 2 —NH 2 ; P2 is an amino acid selected from the group consisting of Gly, Pro, Ala, Val, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg and His or one of the respective N-alkyl amino acids; and
P3 is an amino acid selected from the group consisting of Gly, Pro, Ala, Val, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg and His or one of the respective N-alkyl amino acids.
36. The conjugate according to claim 1 wherein the linker -L- is attached to a cysteine side chain or a cysteine residue and has the formula below:
wherein
§ represents the bond to the drug molecule and
§§ represents the bond to the antibody or antigen-binding fragment thereof,
m is 0, 1, 2, or 3;
n is 0, 1 or 2;
p is 0 to 20; and
L3 is the group
wherein
o is 0 or 1; and
G3 is a straight-chain or branched hydrocarbyl chain having 1 to 100 carbon atoms composed of aryl groups and/or straight-chain and/or branched and/or cyclic alkyl groups, which may be singly or multiply interrupted by one or more of the groups —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —C(═O)—, —NH—C(═O)—, —C(═O)—NH— and a 5- to 10-membered aromatic or nonaromatic heterocycle having up to 4 heteroatoms selected from the group consisting of N, O and S, —NMe-, —NHNH—, —S(═O) 2 —NHNH—, —C(═O)—NHNH—, —S(═O)— and —S(═O) 2 —, wherein the side chains, if present, may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, -sulphone, sulphoxide or sulphonic acid.
37. The conjugate according to claim 36 , wherein the linker -L- is attached to a cysteine side chain or a cysteine residue and has the formula below:
wherein
§ represents the bond to the drug molecule, and
§§ represents the bond to the antibody or antigen-binding fragment thereof,
m is 1;
p is 0;
n is 0; and
L3 is the group
wherein
o is 0 or 1; and
G3 is —(CH 2 CH 2 O) s (CH 2 ) t (CONH) u CH 2 CH 2 O) v (CH 2 ) w —, wherein
s, t, v and w each independently of one another is from 0 to 20 and
u is 0 or 1.
38. The conjugate according to claim 1 , wherein R 2 or R 3 is -L-#1.
39. The conjugate according to claim 38 , wherein the conjugate has a formula selected from the group consisting of:
wherein
X 1 is N, X 2 is N and X 3 is C; 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;
AK 1 is a antibody or antigen-binding fragment thereof attached via a sulphur atom of the antibody or antigen-binding fragment thereof,
n is a number from 1 to 20; and
L 1 is a straight-chain or branched hydrocarbyl 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 —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —C(═O)—, —C(═O)—NH—, —NH—C(═O)—, —NMe-, —NHNH—, —S(═O) 2 —NHNH—, —C(═O)—NHNH— groups and a 5- to 10-membered aromatic or nonaromatic heterocycle having up to 4 heteroatoms selected from the group consisting of N, O and S, —S(═O)— or —S(═O) 2 —, wherein the side chains, if present, may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , —NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid,
L2 and L3 is a straight-chain or branched hydrocarbyl 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 singly or multiply interrupted 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 the group consisting of N, O and S, —S(═O)— or —S(═O) 2 —, wherein the side chains, if present, may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , —NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid, and
wherein the conjugate satisfies one of the following formulae, wherein
SG 1 is a cleavable group,
AK 1 is an antibody or antigen-binding fragment thereof joined via cysteine.
40. The conjugate according to claim 23 , wherein the anti-TWEAKR antibody is an agonistic antibody.
41. The conjugate according to claim 23 , wherein the anti-TWEAKR antibody or the antigen-binding fragment thereof comprises:
a variable heavy chain comprising:
a. a CDR1 of the heavy chain encoded by an amino acid sequence comprising the formula PYPMX (SEQ ID NO: 171), wherein X is I or M;
b. a CDR2 of the heavy chain encoded by an amino acid sequence comprising the formula YISPSGGXTHYADSVKG (SEQ ID NO: 172), wherein X is S or K; and
c. a CDR3 of the heavy chain encoded by an amino acid sequence comprising the formula GGDTYFDYFDY (SEQ ID NO: 173);
and a variable light chain comprising:
d. a CDR1 of the light chain encoded by an amino acid sequence comprising the formula RASQSISXYLN (SEQ ID NO: 174), wherein X is G or S;
e. a CDR2 of the light chain encoded by an amino acid sequence comprising the formula XASSLQS (SEQ ID NO: 175), wherein X is Q, A or N; and
f. a CDR3 of the light chain encoded by an amino acid sequence comprising the formula QQSYXXPXIT (SEQ ID NO: 176), wherein X at position 5 is T or S, X at position 6 is T or S and X at position 8 is G or F.
42. The conjugate according to claim 23 , wherein the anti-TWEAKR antibody or the antigen-binding fragment thereof comprises:
a. a variable sequence of the heavy chain, as shown in SEQ ID NO:10, and also a variable sequence of the light chain, as shown in SEQ ID NO:9, or
b. a variable sequence of the heavy chain, as shown in SEQ ID NO:20, and also a variable sequence of the light chain, as shown in SEQ ID NO:19, or
c. a variable sequence of the heavy chain, as shown in SEQ ID NO:30, and also a variable sequence of the light chain, as shown in SEQ ID NO:29, or
d. a variable sequence of the heavy chain, as shown in SEQ ID NO:40, and also a variable sequence of the light chain, as shown in SEQ ID NO:39, or
e. a variable sequence of the heavy chain, as shown in SEQ ID NO:50, and also a variable sequence of the light chain, as shown in SEQ ID NO:49, or
f. a variable sequence of the heavy chain, as shown in SEQ ID NO:60, and also a variable sequence of the light chain, as shown in SEQ ID NO:59, or
g. a variable sequence of the heavy chain, as shown in SEQ ID NO:70, and also a variable sequence of the light chain, as shown in SEQ ID NO:69, or
h. a variable sequence of the heavy chain, as shown in SEQ ID NO:80, and also a variable sequence of the light chain, as shown in SEQ ID NO:79, or
i. a variable sequence of the heavy chain, as shown in SEQ ID NO:90, and also a variable sequence of the light chain, as shown in SEQ ID NO:89, or
j. a variable sequence of the heavy chain, as shown in SEQ ID NO:100, and also a variable sequence of the light chain, as shown in SEQ ID NO:99, or
k. a variable sequence of the heavy chain, as shown in SEQ ID NO:110, and also a variable sequence of the light chain, as shown in SEQ ID NO:109, or
l. a variable sequence of the heavy chain, as shown in SEQ ID NO:120, and also a variable sequence of the light chain, as shown in SEQ ID NO:119.
43. The conjugate according to claim 1 , wherein the antibody is an IgG antibody.
44. The conjugate according to claim 23 , wherein the anti-TWEAKR antibody comprises:
a. a sequence of the heavy chain as shown in SEQ ID NO:2, and a sequence of the light chain as shown in SEQ ID NO:1 or
b. a sequence of the heavy chain as shown in SEQ ID NO: 12, and a sequence of the light chain as shown in SEQ ID NO:11 or
c. a sequence of the heavy chain as shown in SEQ ID NO:22, and a sequence of the light chain as shown in SEQ ID NO:21 or
d. a sequence of the heavy chain as shown in SEQ ID NO:32, and a sequence of the light chain as shown in SEQ ID NO:31 or
e. a sequence of the heavy chain as shown in SEQ ID NO:42, and a sequence of the light chain as shown in SEQ ID NO 41 or
f. a sequence of the heavy chain as shown in SEQ ID NO: 52, and a sequence of the light chain as shown in SEQ ID NO: 51 or
g. a sequence of the heavy chain as shown in SEQ ID NO:62, and a sequence of the light chain as shown in SEQ ID NO:61 or
h. a sequence of the heavy chain as shown in SEQ ID NO:72, and a sequence of the light chain as shown in SEQ ID NO:71 or
i. a sequence of the heavy chain as shown in SEQ ID NO: 82, and a sequence of the light chain as shown in SEQ ID NO: 81 or
j. a sequence of the heavy chain as shown in SEQ ID NO: 92, and a sequence of the light chain as shown in SEQ ID NO: 91 or
k. a sequence of the heavy chain as shown in SEQ ID NO:102, and a sequence of the light chain as shown in SEQ ID NO:101 or
l. a sequence of the heavy chain as shown in SEQ ID NO: 112, and a sequence of the light chain as shown in SEQ ID NO:111.
45. The conjugate according to claim 1 , wherein the conjugate has 1 to 10 drug molecules or prodrug molecules per antibody or antigen-binding fragment thereof.
46. The conjugate according to claim 1 , wherein the conjugate is an antibody-prodrug conjugate having a formula selected from the group consisting of:
wherein
n is a number from 1 to 20, and
AK 1 is a cysteine-bonded antibody.
47. The conjugate according to claim 1 , wherein the conjugate is an antibody-prodrug conjugate, wherein
n is a number from 1 to 20, and
AK1 is a cysteine-bonded antibody,
wherein the antibody-prodrug conjugate, if it has a group
is bonded to the antibody, may also be present instead of this group at least partially in the form of the hydrolysed open-chain succinamides joined to the antibody.
48. A pharmaceutical composition comprising a conjugate according to claim 1 in combination with an inert non-toxic pharmaceutically suitable auxiliary.
49. A method for the treatment or prophylaxis of diseases, the method comprising administering to a patient in need thereof a conjugate according to claim 1 .
50. A method for the treatment or prophylaxis of hyperproliferative or angiogenic disorders, the method comprising administering to a patient in need thereof a conjugate according to claim 1 .
51. A kinesin spindle protein inhibitor prodrug of the following formula (III):
wherein
X 1 is N, X 2 is N and X 3 is C; 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;
R 1 is —H, -MOD or —(CH 2 ) 0-3 Z,
wherein Z is —H, —NHY 3 , —OY 3 , —SY 3 , halogen, —C(═O)—NY 1 Y 2 or —C(═O)—OY 3 ,
wherein 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′,
wherein Y 3 is —H or —(CH 2 ) 0-3 Z′,
wherein Z′ is —H, NH 2 , SO 3 H, —COOH, —NH—C(═O)—CH 2 —CH 2 —CH(NH 2 )COOH or —(C(═O)—NH—CHY 4 ) 1-3 COOH,
wherein W is —H or —OH,
wherein Y 4 is straight-chain or branched C 1-6 -alkyl which is optionally substituted by —NH—C(═O)—NH 2 , or is aryl or benzyl which are optionally substituted by —NH 2 ;
R 2 is —H, -MOD, —C(═O)—CHY 4 —NHY 5 or —(CH 2 ) 0-3 Z,
wherein Z is —H, halogen, —OY 3 , —SY 3 , —NHY 3 , —C(═O)—NY 1 Y 2 or —C(═O)—OY 3 ,
wherein Y 1 and Y 2 are independently —H, —NH 2 or —(CH 2 ) 0-3 Z′,
wherein Y 3 is —H or —(CH 2 ) 0-3 Z′,
wherein Z′ is —H, —SO 3 H, —NH 2 or —COOH;
wherein Y 4 is straight-chain or branched C 1-6 -alkyl which is optionally substituted by —NH—C(═O)—NH 2 , or is aryl or benzyl which are optionally substituted by —NH 2 ,
wherein Y 5 is —H or —C(═O)—CHY 6 —NH 2 ,
wherein Y 6 is straight-chain or branched C 1-6 -alkyl;
R 4 is a legumain cleavable group of the formula
R 21 —(C═O) (0-1) —(P3) (0-2) -P2—NH—CH(CH 2 C(═O)—NH 2 )—C(═O)—,
wherein R 21 is a C 1-10 -alkyl, C 5-10 -aryl or C 6-10 -aralkyl, C 5-10 -heteroalkyl, C 1-10 -alkyl-O—C 6-10 -aryl, C 5-10 -heterocycloalkyl, heteroaryl, heteroarylalkyl, 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 5-10 -heterocycloalkoxy group which may be mono- or polysubstituted by —NH 2 , —NH-alkyl, —N(alkyl) 2 , —NH—C(═O)-alkyl, —N(alkyl)-C(═O)-alkyl, —SO 3 H, —S(═O) 2 —NH 2 , —S(═O) 2 —N(alkyl) 2 , —COOH, —C(═O)—NH 2 , —C(═O)—N(alkyl) 2 , or —OH, —H or an —O x —(CH 2 CH 2 O) v —R 22 group,
wherein x is 0 or 1,
wherein v is a number from 1 to 20,
wherein R 22 is —H, -alkyl, —CH 2 —COOH, —CH 2 —CH 2 —COOH, or —CH 2 —CH 2 —NH 2 );
P2 is an amino acid selected from the group consisting of Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, citrulline and His or one of the respective N-alkyl amino acids;
P3 is an amino acid selected from the group consisting of Gly, Pro, Ala, Val, Nva, Leu, Ile, Met, Phe, Tyr, Trp, Ser, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, citrulline and His or one of the respective N-alkyl amino acids;
A is —C(═O)—, —S(═O)—, —S(═O) 2 —, —S(═O) 2 —NH— or —C(═N—NH 2 )—;
R 3 is -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, heterocycloalkyl group, a C 1-10 -alkyl, C 6-10 -aryl or C 6-10 -aralkyl, C 5-10 -heteroalkyl, C 1-10 -alkyl-O—C 6-10 -aryl or C 5-10 -heterocycloalkyl group which may be 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—C(═O)—NH-alkyl groups, 1-3 —NH—C(═O)-alkyl groups, 1-3 —NH—C(═O)—NH-alkyl groups, 1-3 —S(═O) n -alkyl groups, 1-3 —S(═O) 2 —NH-alkyl groups, 1-3 —NH-alkyl groups, 1-3 —N(alkyl) 2 groups, 1-3 —NH 2 groups or 1-3 —(CH 2 ) 0-3 Z groups, wherein
wherein Z is —H, halogen, —OY 3 , —SY 3 , —NHY 3 , —C(═O)—NY 1 Y 2 or —C(═O)—OY 3 ,
wherein n is 0, 1 or 2,
wherein Y 1 and Y 2 are independently —H, —NH 2 or —(CH 2 ) 0-3 Z′,
wherein Y 3 is —H, —(CH 2 ) 0-3 —CH(NH—C(═O)—CH 3 )Z′, —(CH 2 ) 0-3 —CH(NH 2 )Z′, or —(CH 2 ) 0-3 Z′,
wherein Z′ is —H, —SO 3 H, —NH 2 or —COOH,
R 5 is —H, —NH 2 , —NO 2 , halogen, —CN, —CF 3 , —OCF 3 , —CH 2 F, —CH 2 F, —SH or —(CH 2 ) 0-3 Z,
wherein Z is —H, —OY 3 , —SY 3 , halogen, —NHY 3 , —C(═O)—NY 1 Y 2 or —C(═O)—OY 3 ,
wherein Y 1 and Y 2 are independently —H, —NH 2 or —(CH 2 ) 0-3 Z′,
wherein Y 3 is —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, 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, hydroxy, —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 )
wherein HZ 2 is a 4- to 7-membered heterocycle having up to two heteroatoms selected from the group consisting of N, O and S, wherein each of these groups 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-H,
wherein
R 1 ° 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 and/or branched hydrocarbon group which has 1 to 10 carbon atoms and which may be interrupted once or more than once identically or differently by the groups —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)—, —CR x ═N—O—,
wherein R x is —H, C 1 -C 3 -alkyl or phenyl,
wherein 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 , NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid), wherein the hydrocarbon chain including any side chains may be substituted by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid, wherein the group -MOD has at least one group —COOH;
or a salt, a solvate, a salt of the solvate, or an epimer thereof.