Antibody drug conjugates with enzymatically cleavable groups

Patent metadata

Field	Value
Publication number	US-12144865-B2
Application number	US-202117374756-A
Country	US
Kind code	B2
Filing date	Jul 13, 2021
Priority date	Jun 22, 2015
Publication date	Nov 19, 2024
Grant date	Nov 19, 2024

Abstract

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.

First claim

The invention claimed is:

1. A conjugate of an antibody or antigen-binding fragment thereof with one or more drug molecules, of the following formula:

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):

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 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 -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, or 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 —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
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, 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) 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, 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 , and R 4 is -L- #1, or R 8 comprises -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 R 4 comprises a legumain cleavable group of the formula:
(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, 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.

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

Assignees

• Bayer Pharma AG

Inventors

• Lerchen Hans-Georg
• Rebstock Anne-Sophie
• Cancho Grande Yolanda
• Marx Leo
• Stelte-Ludwig Beatrix
• Terjung Carsten
• Mahlert Christoph
• Greven Simone
• Sommer Anette
• Berndt Sandra

Classifications

• A61K47/6803 Primary

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/4025

  not condensed and containing further heterocyclic rings, e.g. cromakalim · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title