Antibody drug conjugates (ADCs) having enzymatically cleavable groups

Patent metadata

Field	Value
Publication number	US-11660351-B2
Application number	US-201716472749-A
Country	US
Kind code	B2
Filing date	Dec 14, 2017
Priority date	Dec 21, 2016
Publication date	May 30, 2023
Grant date	May 30, 2023

Abstract

The invention relates to novel binder-drug conjugates (ADCs) having improved properties, to active metabolites of these ADCs and to processes for their preparation. The present invention furthermore relates to the use of these conjugates for the treatment and/or prevention of diseases and to the use of these conjugates for preparing medicaments for treatment and/or prevention of diseases, in particular hyperproliferative and/or angiogenic disorders such as, for example, cancer diseases.

First claim

The invention claimed is:

1. An antibody-drug conjugate of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
AK is an antibody or an antigen-binding antibody fragment thereof;
n is a number from 1 to 50;
X 1 is N,
X 2 is N and
X 3 is C;

or
X 1 is N,
X 2 is C and
X 3 is N;

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 methyl;
R 2 is methyl, ethyl, —CH 2 —CH(CH 3 ) 2 , —CH 2 —C(═O)OH or isopropyl;
R 3 is methyl, ethyl, —CH 2 —CH(CH 3 ) 2 or —CH 2 —C(═O)—NH 2 ; and
M is the group
#—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —NH—C(═O)—CH 2 —CH(##)-COOH,
#—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —NH—C(═O)—CH(##)—CH 2 —COOH,
#—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —W,
#—C(═O)—CH 2 —NH—C(═O)—CH 2 —CH(##)-COOH,
#—C(═O)—CH 2 —NH—C(═O)—CH(##)—CH 2 —COOH,
#—C(═O)—CH 2 —W,
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 2-8 —C(═O)-###,
#—C(═O)—(CH 2 ) 3 —C(═O)-###,
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 5 —W,
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 )-##, or
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 —CH 2 —O) 1-8 —(CH 2 ) 2 —NH—C(═O)—CH 2 -##;
wherein:
# represents the bond to —NR 1 —,
W is the group:

## represents the bond to a sulfur atom of a cysteine side-chain of the antibody or antigen-binding antibody fragment thereof; and
### represents the bond to a nitrogen atom of a lysine side-chain of the antibody or antigen-binding antibody fragment thereof,

wherein the antibody or antigen-binding antibody fragment binds to CD123.

2. The antibody-drug conjugate of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein:
X 1 is CH,
X 2 is C,
X 3 is N;
R 1 is methyl;
R 2 is methyl, —CH 2 —CH(CH 3 ) 2 , —CH 2 —C(═O)OH or isopropyl;
R 3 is methyl, —CH 2 —CH(CH 3 ) 2 or —CH 2 —C(═O)—NH 2 ; and
M is the group:
#—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —NH—C(═O)—CH 2 —CH(##)-COOH,
#—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —NH—C(═O)—CH(##)—CH 2 —COOH,
#—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —W,
#—C(═O)—CH 2 —NH—C(═O)—CH 2 —CH(##)-COOH,
#—C(═O)—CH 2 —NH—C(═O)—CH(##)—CH 2 —COOH,
#—C(═O)—CH 2 —W,
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 3 —C(═O)-###,
#—C(═O)—(CH 2 ) 3 —C(═O)-###,
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 5 —W,
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 )-##, or
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 —CH 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—CH 2 -##.

3. The antibody-drug conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is methyl;
R 3 is methyl, —CH 2 —CH(CH 3 ) 2 , or —CH 2 —C(═O)—NH 2 ;
M is the group
#—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —NH—C(═O)—CH 2 —CH(##)-COOH,
#—C(═O)—CH(CH 3 )—NH—C(═O)—CH 2 —NH—C(═O)—CH(##)—CH 2 —COOH,
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 3 —C(═O)-###;
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 5 —W,
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 )-##, or
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 —CH 2 —O) 4 —(CH 2 ) 2 —NH—C(═O)—CH 2 -##.

4. The antibody-drug conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is methyl;
R 3 is —CH 2 —C(═O)—NH 2 ;
M is the group:
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 3 —C(═O)-###; or
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 5 —W.

5. The antibody-drug conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
n is a number from 1 to 20;
R 2 is methyl;
R 3 is —CH 2 —C(═O)—NH 2 ;
M is the group
#—C(═O)—CH(CH 3 )—NH—C(═O)—(CH 2 ) 3 —C(═O)-###.

6. The antibody-drug conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the antibody-drug conjugate has a structure selected from the group consisting of

wherein
AK1 is the antibody or antigen-binding fragment thereof, which is attached via a sulfur atom of a cysteine side-chain,
AK2 is the antibody or antigen-binding fragment thereof, which is attached via a nitrogen atom of a lysine side-chain, and
n is a number from 1 to 50.

7. The antibody-drug conjugate of claim 6 , or a pharmaceutically acceptable salt thereof, wherein n is a number from 1 to 20.

8. The antibody-drug conjugate of claim 7 , a pharmaceutically acceptable salt thereof, wherein n is a number from 1 to 8.

9. The antibody-drug conjugate of claim 8 , or a pharmaceutically acceptable salt thereof, wherein n is a number from 4 to 8.

10. The antibody-drug conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the antibody or the antigen-binding antibody fragment thereof, after binding to CD123, is internalized by the target cell through the binding.

11. A pharmaceutical composition comprising at least one antibody-drug conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with an inert, non-toxic, pharmaceutically suitable auxiliary.

12. The antibody-drug conjugate of claim 1 , wherein the antibody or antigen-binding antibody fragment comprises a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 82, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 83, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 84; and a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 86, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 87, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 88.

13. The antibody-drug conjugate of claim 12 , wherein the variable heavy chain comprises SEQ ID NO: 81 and the variable light chain comprises SEQ ID NO: 85.

14. The antibody-drug conjugate of claim 12 , wherein the antibody or antigen-binding fragment comprises a heavy chain comprising SEQ ID NO: 89 and a light chain comprising SEQ ID NO: 90.

15. The antibody-drug conjugate of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the antibody-drug conjugate has the structure:

16. The antibody-drug conjugate of claim 15 , wherein the antibody or antigen-binding antibody fragment comprises a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 82, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 83, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 84; and a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 86, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 87, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 88.

17. The antibody-drug conjugate of claim 16 , wherein the variable heavy chain comprises SEQ ID NO: 81 and the variable light chain comprises SEQ ID NO: 85.

18.

Assignees

• Bayer Pharma AG
• Bayer Ag

Inventors

• Lerchen Hans-Georg
• Rebstock Anne-Sophie
• Stelte-Ludwig Beatrix
• Kirchhoff Dennis
• Dietz Lisa
• Mahlert Christoph
• Greven Simone
• Märsch Stephan
• Berndt Sandra
• Sommer Anette
• Hammer Stefanie

Classifications

• A61K47/6889 Primary

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/68 Primary

  the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment · CPC title

• A61P43/00

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

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title