Pyrrolobenzodiazepine antibody drug conjugates and methods of use

Patent metadata

Field	Value
Publication number	US-10058613-B2
Application number	US-201615281830-A
Country	US
Kind code	B2
Filing date	Sep 30, 2016
Priority date	Oct 2, 2015
Publication date	Aug 28, 2018
Grant date	Aug 28, 2018

Abstract

The invention provides antibody-drug conjugates comprising an antibody conjugated to a pyrrolobenzodiazepine drug moiety via a disulfide linker, pyrrolobenzodiazepine linker-drug intermediates, and methods of using the antibody-drug conjugates.

First claim

We claim:

1. A linker-drug intermediate of Formula I:

wherein X -- Y is selected from the group consisting of CH 2 —CH 2 , CH═CH, C(═O)NH, and CH 2 —NH;
A is a 5-membered or 6-membered heterocyclic ring, optionally substituted with F, C 1 -C 6 alkyl, or ═C(R) 2 where R is independently H, F, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
R 1 and R 2 are independently selected from the group consisting of H and C 1 -C 6 alkyl, or R 1 and R 2 form a 3, 4, 5, or 6-membered cycloalkyl or heterocyclyl group;
each R 3 is independently selected from the group consisting of NO 2 , Cl, F, CN, CO 2 H and Br; and
m is 1 or 2.

2. The linker-drug intermediate of claim 1 of Formula Ia:

3. The linker-drug intermediate of claim 1 of Formula Ib:

4. The linker-drug intermediate of claim 1 having Formula Ic:

wherein R 4 and R 5 are each H, or R 4 and R 5 are ═O.

5. The linker-drug intermediate of claim 1 of Formula Id:

wherein R 4 and R 5 are each H, or R 4 and R 5 are ═O.

6. The linker-drug intermediate of claim 5 wherein R 4 and R 5 are each H.

7. The linker-drug intermediate of claim 1 of Formula Ie:

8. The linker-drug intermediate of claim 1 wherein X -- Y is C(═O)—NH.

9. The linker-drug intermediate of claim 1 of Formula If:

10. The linker-drug intermediate of claim 1 wherein R 1 and R 2 along with the carbon atom to which they are attached form cyclopropyl or cyclobutyl ring.

Assignees

• Genentech Inc

Inventors

• DRAGOVICH Peter
• Pillow Thomas
• Sadowsky Jack
• Sliwkowski Mark X
• Wei Binqing

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61K47/6851

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