US 12,144,865 B2
Antibody drug conjugates with enzymatically cleavable groups
Hans-Georg Lerchen, Leverkusen (DE); Anne-Sophie Rebstock, Champagne au Mont d'Or (FR); Yolanda Cancho Grande, Leverkusen (DE); Leo Marx, Wuppertal (DE); Beatrix Stelte-Ludwig, Wülfrath (DE); Carsten Terjung, Bochum (DE); Christoph Mahlert, Wuppertal (DE); Simone Greven, Dormagen (DE); Anette Sommer, Berlin (DE); and Sandra Berndt, Hohen Neuendorf (DE)
Assigned to BAYER PHARMA AKTIENGESELLSCHAFT, Berlin (DE)
Filed by BAYER PHARMA AKTIENGESELLSCHAFT, Berlin (DE)
Filed on Jul. 13, 2021, as Appl. No. 17/374,756.
Application 17/374,756 is a continuation of application No. 15/739,111, granted, now 11,123,439, issued on Sep. 21, 2021, previously published as PCT/EP2016/064118, filed on Jun. 20, 2016.
Claims priority of application No. 15173102 (EP), filed on Jun. 22, 2015; and application No. 16160738 (EP), filed on Mar. 16, 2016.
Prior Publication US 2023/0039341 A1, Feb. 9, 2023
Int. Cl. A61K 47/68 (2017.01); A61K 31/4025 (2006.01); A61K 31/4439 (2006.01); A61K 47/65 (2017.01)
CPC A61K 47/6803 (2017.08) [A61K 31/4025 (2013.01); A61K 31/4439 (2013.01); A61K 47/65 (2017.08); A61K 47/6849 (2017.08); A61K 47/6851 (2017.08); A61K 47/6855 (2017.08); A61K 47/6857 (2017.08); A61K 47/6863 (2017.08); A61K 47/6865 (2017.08); A61K 2300/00 (2013.01)] 33 Claims
OG exemplary drawing
 
1. A conjugate of an antibody or antigen-binding fragment thereof with one or more drug molecules, of the following formula:

OG Complex Work Unit Chemistry
wherein
BINDER is the antibody or antigen-binding fragment thereof,
L is a linker, wherein -L- is attached to a lysine 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, wherein -L-KSP has the following formula (IIa):

OG Complex Work Unit Chemistry
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;
R1 is —H, -L- #1, -MOD or —(CH2)0-3Z,
wherein Z is —H, —NHY3, —OY3, —SY3, halogen, —C(═O)—NY1Y2 or -CO-OY3,
wherein Y1 and Y2 are independently —H, —NH2, —(CH2CH2O)0-3—(CH2)0-3Z′ or —CH(CH2W)Z′,
wherein Y3 is —H or —(CH2)0-3Z′,
wherein Z′ is —H, NH2, SO3H, —COOH, —NH—C(═O)—CH2—CH2—CH(NH2)COOH or —(C(═O)—NH—CHY4)1-3COOH,
wherein W is —H or —OH,
wherein Y4 is straight-chain or branched C1-6-alkyl which is optionally substituted by —NH—C(═O)—NH2, or is aryl or benzyl which are optionally substituted by —NH2;
R2 is -L- #1, —H, -MOD, —C(═O)—CHY4—NHY5 or —(CH2)0-3Z,
wherein Z is —H, halogen, —OY3, —SY3, —NHY3, —C(═O)—NY1Y2 or —C(═O)—OY3,
wherein Y1 and Y2 are independently —H, —NH2 or —(CH2)0-3Z′,
wherein Y3 is —H or —(CH2)0-3Z′,
wherein Z′ is —H, —SO3H, —NH2 or —COOH;
wherein Y4 is straight-chain or branched C1-6-alkyl which is optionally substituted by —NH—C(═O)—NH2, or is aryl or benzyl which are optionally substituted by —NH2,
wherein Y5 is —H or —C(═O)—CHY6—NH2,
wherein Y6 is straight-chain or branched C1-6-alkyl;
R4 is -L- #1, or a group of the formula
R21—(C(═O))(0-1)-(P3)(0-2)-P2—NH—CH(CH2C(═O)—NH2)—C(═O)— or
R21—(C(═O))(0-1)-(P3)(0-2)-P2—NH-CH(CH2COOH)—C(═O)—,
wherein R21 is a C1-10-alkyl, C5-aryl or C6-10-aralkyl, C5-10-heteroalkyl, C1-10-alkyl-O—C6-10-aryl, C5-10-heterocycloalkyl, heteroaryl, heteroarylalkyl, C1-10-alkoxy, C6-10-aryloxy or C6-10-aralkoxy, C5-10-heteroalkoxy, C1-10-alkyl-O—C6-10-aryloxy, C5-10-heterocycloalkoxy group which may be mono- or polysubstituted by —NH2, —NH-alkyl, —N(alkyl)2, NH—C(═O)-alkyl, —N(alkyl)-C(═O)-alkyl, —SO3H, —S(═O)2NH2, —S(═O)2—N(alkyl)2, —COOH, —C(═O)NH2, —C(═O)N(alkyl)2, or —OH, —H or an —Ox—(CH2CH2O)y—R22 group,
wherein x is 0 or 1
wherein v is a number from 1 to 20, and
wherein R22 is —H, -alkyl, —CH2—COOH, —CH2—CH2—COOH, or —CH2—CH2—NH2,
wherein P2 is an amino acid selected from the group consisting of Gly, L-Pro, L-Ala, L-Val, L-Nva, L-Leu, L-Ile, L-Met, L-Phe, L-Tyr, L-Trp, L-Ser, L-Thr, L-Cys, L-Asn, L-Gln, L-Asp, L-Glu, L-Lys, L-Arg, L-citrulline and L-His;
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 is —C(═O)—, —S(═O)—, —S(═O)2—, —S(═O)2NH— or —C(═N—NH2)—;
R3 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, 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 —NH2 groups or 1-3 —(CH2)0-3Z groups,
wherein Z is —H, halogen, —OY3, —SY3, —NHY3, —C(═O)—NY1Y2 or —C(═O)—OY3,
wherein n is 0, 1 or 2,
wherein Y1 and Y2 are independently —H, —NH2 or —(CH2)0-3Z′,
wherein Y3 is —H, —(CH2)0-3—CH(NHCOCH3)Z′, —(CH2)0-3—CH(NH2)Z′ or —(CH2)0-3Z′,
wherein Z′ is —H, —SO3H, —NH2 or —COOH;
R5 is —H, —NH2, —NO2, halogen, —CN, —CF3, —OCF3, —CH2F, —CH2F, —SH or —(CH2)0-3Z,
wherein Z is —H, —OY3, —SY3, halogen, —NHY3, —C(═O)—NY1Y2 or —C(═O)—OY3,
wherein Y1 and Y2 are independently —H, —NH2 or —(CH2)0-3Z′,
wherein Y3 is —H or —(CH2)0-3Z′,
wherein Z′ is —H, —SO3H, —NH2 or —COOH;
R6 and R7 are independently —H, cyano, C1-10-alkyl, fluoro-C1-10-alkyl, C2-10-alkenyl, fluoro-C2-10-alkenyl, C2-10-alkynyl, fluoro-C2-10-alkynyl, hydroxy, —NO2, NH2, —COOH or halogen,
R8 is C1-10-alkyl, fluoro-C1-10-alkyl, C2-10-alkenyl, fluoro-C2-10-alkenyl, C2-10-alkynyl, fluoro-C2-10-alkynyl, C4-10-cycloalkyl, fluoro-C4-10-cycloalkyl, or —(CH2)0-2—(HZ2),
wherein HZ2 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 —NH2 or -L- #1;
R9 is —H, —F, —CH3, —CF3, —CH2F or —CHF2;
wherein one of the substituents R1, R2, R3, and R4 is -L- #1, or R8 comprises -L- #1,
L- is the linker and #1 is the bond to the antibody or antigen-binding fragment thereof,
wherein -MOD is —(NR10)n-(G1)o-G2-G3,
wherein R10 is —H or C1-C3-alkyl;
wherein G1 is —NH—C(═O)—, —C(═O)NH— or

OG Complex Work Unit Chemistry
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, —NRy—, —NRyC(═O)—, —C(═O)—NRy—, —NRyNRy—, —S(═O)2NRyNRy—, —C(═O)—NRyNRy—, —C(═O)—, or —CRx═N—O—,
wherein Ry is —H, phenyl, C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkynyl, each of which may be substituted by —NH—C(═O)—NH2, —COOH, —OH, —NH2, —NH—CN—NH2, sulphonamide, sulphone, sulphoxide or sulphonic acid
wherein Rx is —H, C1-C3-alkyl or phenyl,
wherein the hydrocarbon chain including a C1-C10-alkyl group optionally substituted on the hydrocarbon group as side chain, if present, may be substituted by —NH—C(═O)—NH2, —COOH, —OH, —NH2, —NH—CN—NH2, sulphonamide, sulphone, sulphoxide or sulphonic acid,
wherein G3 is —H or —COOH;
wherein -MOD has at least one —COOH group,
wherein R4 comprises a legumain cleavable group of the formula:
(C═O)(0-1)—(P3)(0-2)-P2—NH-CH(CH2C(═O)—X)-C(═O)—,
wherein X is —NH2 or —COOH;
wherein P2 is an amino acid selected from the group consisting of Gly, L-Pro, L-Ala, L-Val, L-Nva, L-Leu, L-Ile, L-Met, L-Phe, L-Tyr, L-Trp, L-Ser, L-Thr, L-Cys, L-Asn, L-Gln, L-Asp, L-Glu, L-Lys, L-Arg, L-citrulline and L-His;
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.