Antibody-drug conjugates (ADCs) of KSP inhibitors with aglycosylated anti-TWEAKR antibodies

Patent metadata

Field	Value
Publication number	US-10485880-B2
Application number	US-201515536112-A
Country	US
Kind code	B2
Filing date	Dec 10, 2015
Priority date	Dec 15, 2014
Publication date	Nov 26, 2019
Grant date	Nov 26, 2019

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 aglycosylated anti-TWEAKR antibody,
L is a linker, n is a number from 1 to 50, and
KSP is a compound of the formula (I) below:

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, —CO—NY 1 Y 2 or —CO—OY 3 , wherein
Y 1 and Y 2 are independently of one another represent H, NH 2 , —(CH 2 CH 2 O) 0-3 —(CH 2 ) 0-3 Z′ or —CH(CH 2 W)Z′, and
Y 3 is H or —(CH 2 ) 0-3 Z′,
wherein Z′ is H, NH 2 , SO 3 H, COOH, —NH—CO—CH 2 —CH 2 —CH(NH 2 )COOH or —(CO—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 —NHCONH 2 , or is aryl or benzyl which are optionally substituted by —NH 2 ;

R 2 is H, -MOD, —CO—CHY 4 —NHY 5 or —(CH 2 ) 0-3 Z, wherein Z is —H, halogen, —OY 3 , —SY 3 , NHY 3 , —CO—NY 1 Y 2 or —CO—OY 3 , wherein
Y 1 and Y 2 are independently H, NH 2 or —(CH 2 ) 0-3 Z′, and
Y 3 is H or —(CH 2 ) 0-3 Z′,
wherein 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 —NHCONH 2 , or is aryl or benzyl which are optionally substituted by —NH 2 , and
Y 5 is s H or CO—CHY 6 —NH 2 , wherein Y 6 is straight-chain or branched C 1-6 -alkyl;

R 4 is H, -L-#1, -SG lys -(CO) 0-1 —R 4′ , —CO—CHY 4 —NHY 5 or —(CH 2 ) 0-3 Z, wherein
SG lys is a group cleavable by lysosomal enzymes,
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—CO-alkyl, N(alkyl)-CO-alkyl, —SO 3 H, —SO 2 NH 2 , —SO 2 —N(alkyl) 2 , —COOH, CONH 2 , —CON(alkyl) 2 or —OH, or
R 4′ is —H or a group —O x —(CH 2 CH 2 O) y —R 4″ , wherein
x is 0 or 1, and
y is a number from 1 to 10, and
R 4″ is —H, -alkyl, CH 2 —COOH, CH 2 —CH 2 —COOH, or CH 2 —CH 2 —NH 2 ;

Z is —H, halogen, —OY 3 , —SY 3 , NHY 3 , —CO—NY 1 Y 2 or —CO—OY 3 ,
Y 1 and Y 2 are independently H, NH 2 or —(CH 2 ) 0-3 Z′, and
Y 3 is H or —(CH 2 ) 0-3 Z′, wherein 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 —NHCONH 2 , or
Y 4 is aryl or benzyl which are optionally substituted by —NH 2 , and
Y 5 is H or CO CHY 6 —NH 2 , wherein Y 6 is straight-chain or branched C 1-6 -alkyl;

or
R 2 and R 4 together (with formation of a pyrrolidine ring) represent 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, COO(C 1-4 -alkyl) or OH;
A is CO, SO, SO 2 , SO 2 NH or CNNH;
R 3 is -L-#1, -MOD or an optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, 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—CO—NH-alkyl groups, 1-3 —NH—CO-alkyl groups, 1-3 —NH—CO—NH-alkyl groups, 1-3 —S(O) n -alkyl groups, 1-3 —SO 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 , —CO—NY 1 Y 2 or —CO—OY 3 , wherein
Y 1 and Y 2 are H, NH 2 or —(CH 2 ) 0-3 Z′ and
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 , —CO—NY 1 Y 2 or —CO—OY 3 , wherein
Y 1 and Y 2 are independently H, NH 2 or —(CH 2 ) 0-3 Z′, and
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, optionally fluorinated C 1-10 -alkyl, optionally fluorinated C 2-10 -alkenyl, optionally fluorinated C 2-10 -alkynyl, hydroxy, NO 2 , NH 2 , COOH or halogen,
R 8 is optionally fluorinated C 1-10 -alkyl, optionally fluorinated C 2-10 -alkenyl, optionally fluorinated C 2-10 -alkynyl, optionally fluorinated 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, CO 2 H or NH 2 ;
R 9 is H, F, CH 3 , CF 3 , CH 2 F or CHF 2 ;
wherein one of the substituents R 1 , R 3 and R 4 is -L-#1,
L is the linker and #1 is the bond to the antibody,

wherein -MOD is (NR 10 ) n -(G1) o -G2-H, wherein
R 10 is H, NH 2 , or C 1 -C 3 -alkyl;
G1 is —NHCO—, —CONH— or

wherein if G1 is —NHCO— or

R 10 is not NH 2 ;
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 by one or more of the groups —O—, —S—, —SO—, —SO 2 , —NR y —, —NR y CO—, CONR y —, —NR y NR y —, —SO 2 NR y NR y —, —CONR y NR y —, —CO—, or —CR x ═N—O—,
wherein the hydrocarbon chain including any side chains may be substituted by —NHCONH 2 , —COOH, —OH, —NH 2 , NH—CNNH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid;
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 —NHCONH 2 , —COOH, —OH, —NH 2 , NH—CNNH 2 , sulphonamide, sulphone, sulphoxide or sulphonic acid;
wherein Rx is H, C 1 -C 3 -alkyl or phenyl;

or a salt, a solvate, or a salt of the solvate thereof.

2. The conjugate according to claim 1 , wherein
A is CO (carbonyl).

3. The conjugate according to claim 1 , wherein
R 1 is H, -L-#1, —COOH, —CONHNH 2 , —(CH 2 ) 1-3 NH 2 , —CONZ″(CH 2 ) 1-3 NH 2 or —CONZ″CH 2 COOH, wherein
Z″ is H or NH 2 .

4. The conjugate according to claim 1 , wherein
R 2 and R 4 represent 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, Me, CH 2 F, OMe, CH 2 OH, COO(C 1-4 -alkyl) or OH.

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

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

Assignees

• Bayer Pharma AG

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/16

  Amides, e.g. hydroxamic acids · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title