Antibody drug conjugates of kinesin spindel protein (KSP) inhibitors with anti-CD123-antibodies

Patent metadata

Field	Value
Publication number	US-10744205-B2
Application number	US-201615739134-A
Country	US
Kind code	B2
Filing date	Jun 20, 2016
Priority date	Jun 23, 2015
Publication date	Aug 18, 2020
Grant date	Aug 18, 2020

Abstract

The present application relates to novel binder drug conjugates (ADCs), to active metabolites of these ADCs, to processes for preparing these ADCs, to the use of these ADCs for the treatment and/or prophylaxis of diseases and to the use of these ADCs for preparing medicaments for treatment and/or prophylaxis of diseases, in particular hyperproliferative and/or angiogenic disorders such as, for example, cancer diseases. Such treatments can be effected as monotherapy or else in combination with other medicaments or further therapeutic measures.

First claim

The invention claimed is:

1. A conjugate of an antibody with one or more drug molecules of the formula below:

wherein
BINDER is an anti-CD 123 antibody which is a chimeric or humanized variant of the antibody 7G3 or 12F1 or is an antigen-binding fragment thereof;
L is a linker;
n is a number from 1 to 50; and
KSP is a compound of the formula (I) below:
Formula (I):

wherein
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 —C(═O)—OY 3 ,
Y 1 and Y 2 are independently of one another —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 , —SO 3 H, —COOH, —NH—C(═O)—CH 2 —CH 2 —CH(NH 2 )COOH or —(CO—NH—CHY 4 ) 1-3 COOH,
W is H or OH, and
Y 4 is straight-chain or branched C 1-6 alkyl which is optionally substituted by —NH—C(═O)—NH 2 , or represents 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 ,
Y 1 and Y 2 are independently of one another —H, —NH 2 or —(CH 2 ) 0-3 Z′,
Y 3 is —H or —(CH 2 ) 0-3 Z′,
Z′ is —H, —SO 3 H, —NH 2 or —COOH;
Y 4 is straight-chain or branched C 1 -6-alkyl which is optionally substituted by —NH—C(═O)—NH 2 , or represents aryl or benzyl which are optionally substituted by —NH 2 ,
Y 5 is —H or —C(═O)—CHY 6 —NH 2 , and
Y 6 is straight-chain or branched C 1-6 -alkyl;

R 4 is —H, -L-#1, -SG lys -(C═O) 0-1 —R 4′ , —C(═O)—CHY 4 —NHY 5 or —(CH 2 ) 0-3 Z, wherein
SG lys is a group which can be cleaved by lysosomal enzymes,
wherein R 4′ 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, heteroarylalkoxy, C 1-10 -alkoxy, C 6-10 -aryloxy or C 6-10 -aralkoxy,
C 5-10 -heteroaralkoxy, 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 a group —O x —(CH 2 CH 2 O) v —R 4″ ,
wherein x is 0 or 1,
wherein v is a number from 1 to 20,
wherein R 4″ is —H, -alkyl,
—CH 2 —COOH, —CH 2 —CH 2 —COOH, or —CH 2 —CH 2 —NH 2 ;

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 of one another —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 represents aryl or benzyl which are optionally substituted by —NH 2 ,
wherein Y 5 is —H or —C(═O)—CHY 6 —NH 2 , and
wherein Y 6 is straight-chain or branched C 1-6 -alkyl;

or

R 2 and R 4 taken together (with formation of a pyrrolidine ring) are —CH 2 —CHR 11 — or —CHR 11 —CH 2 —,
wherein

R 11 is —H, —NH 2 , —SO 3 H, —COOH, —SH, halogen, C 1-4 -alkyl, C 1-4 -haloalkyl, C 1-4 -alkoxy, hydroxyl-substituted
C 1-4 -alkyl, C(═O)—O—(C 1-4 -alkyl) or —OH;
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, or heterocycloalkyl group,
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
Y 1 and Y 2 are independently of one another —H, —NH 2 or —(CH 2 ) 0-3 Z′,
Y 3 is —H or —(CH 2 ) 0-3 Z′, and
Z′ is —H, —SO 3 H, —NH 2 or —COOH;

R 6 and R 7 are independently of one another —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 -alkyl, 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 ), which may be mono- or disubstituted, identically or differently, by —OH, —COOH or —NH 2 , and
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;

R 9 is —H, —F, —CH 3 , —CF 3 , —CH 2 F or —CHF 2 ;
wherein
one of the substituents R 1 , R 3 or R 4 is -L-#1,

L is the linker and #1 is the bond to the antibody,
MOD is —(NR 10 ) n -(G1) o -G2-G3,
wherein
R 10 is —H or C 1 -C 3 -alkyl;
G1 is —NH—C(═O)— or —C(═O)—NH— (wherein, if G1 is —NH—C(═O)—, R 10 is not —NH 2 );
n is 0 or 1;
o is 0 or 1; and
G2 is a straight-chain or branched hydrocarbon chain 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 —, or —C(═O)—NR y NR y —
wherein
R y is —H, phenyl, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl or C 2 -C 0 o-alkynyl, each of which may be mono- or disubstituted, identically or differently, by —NH—C(═O)—NH 2 , —COOH, —OH, —NH 2 , —NH—CNNH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid,
and/or which may be interrupted once or more than once, identically or differently, by —C(═O)—, —CR x ═N—O—, wherein
R x is —H, C 1 -C 3 -alkyl or phenyl, and

wherein
the hydrocarbon chain including a C 1 -C 10 -alkyl group optionally substituted on the hydrocarbon group as side chain may be substituted by —NH—C(═O)NH 2 , —COOH, —OH, —NH 2 , —NH—CN—NH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid, G3 is —H or —COOH, and
wherein the group -MOD has at least one group —COOH;

or a salt, a solvate, a salt of a solvate, or an epimer thereof.

2. The conjugate according to claim 1 , wherein A is —C(═O)—.

3. The conjugate according to claim 1 , wherein R 1 is —H, -L-#1, —COOH, —C(═O)—NHNH 2 , —(CH 2 ) 1-3 NH 2 ,
—C(═O)—NZ″(CH 2 ) 1-3 NH 2 or —C(═O)—NZ″CH 2 COOH, and wherein Z″ is —H or —NH 2 .

4. The conjugate according to claim 1 , wherein
R 2 and R 4 are —H; or
R 2 and R 4 together (with formation of a pyrrolidine ring) are —CHR 11 —CH 2 — or —CH 2 —CHR 11 —,
wherein R 11 is —H, —COOH, —F, methyl, —CH 2 F, —O-methyl, —CH 2 OH, —C(═O)—O—(C 1-4 -alkyl) or —OH.

5. The conjugate according to claim 1 , wherein
R 3 is -L-#1; or
R 3 is a phenyl group which may be mono- or polysubstituted by halogen, C 1-3 -alkyl or fluoro-C 1-3 -alkyl; or
R 3 is a C 1-10 -alkyl group or fluoro-C1-10-alkyl group which may optionally be substituted by —OY 4 , —SY 4 , —O—C(═O)—Y 4 , —O—C(═O)—NH—Y 4 , —NH—C(═O)—Y 4 , —NH—C(═O)—NH—Y 4 , —S(O) n —Y 4 , —S(═O) 2 —NH—Y 4 , —NH—Y 4 or —N(Y 4 ) 2 ,
wherein
n is 0, 1 or 2, and
Y 4 is —H, phenyl which is optionally mono- or polysubstituted by halogen, C 1-3 -alkyl or fluoro-C 1-3 -alkyl, or is alkyl which may be substituted by
—OH, —COOH and/or —NH—C(═O)—C 1-3 -alkyl.

6. The conjugate according to claim 5 , wherein the conjugate has the formula (IIj) below:

wherein
R 3 is -L-#1;
A is —C(═O)—; and

R 6 and R 7 are independently of one an

Assignees

• Bayer Pharma AG

Inventors

• Lerchen Hans-Georg
• Rebstock Anne-Sophie
• Cancho Grande Yolanda
• Wittrock Sven
• Stelte-Ludwig Beatrix
• Mahlert Christoph
• Greven Simone
• Märsch Stephan
• Kirchhoff Dennis

Classifications

• A61K47/6803 Primary

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

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• C07D207/33

  with substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• A61K31/4025

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

• C07K2317/565

  Complementarity determining region [CDR] · CPC title