Pyrrolobenzodiazepine antibody drug conjugates and methods of use

• US 10,058,613 B2
• Filed: 09/30/2016
• Issued: 08/28/2018
• Est. Priority Date: 10/02/2015
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Dragovich, Peter, Pillow, Thomas, Sadowsky, Jack, Sliwkowski, Mark X., Wei, BinQing
• Primary Examiner(s): Huff, Sheela J.
• Application Number:
  US15/281,830
• Publication Number:
  US 20170095570A1
• Time in Patent Office: 697 Days
• Field of Search: None
• CPC Class Codes: A61K 31/5517 condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/68035 the drug being a pyrrolobenzodiazepine
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6855 the tumour determinant being from breast cancer cell
• CPC Class Codes: A61K 47/6889 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 Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/40 characterized by post-translational modification
• CPC Class Codes: C07K 2317/522 CH1 domain
• CPC Class Codes: C07K 2317/567 Framework region [FR]

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.

Claims

1. A linker-drug intermediate of Formula I:

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:

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

6. The linker-drug intermediate of claim 5 wherein R⁴ and R⁵ 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 R¹ and R² along with the carbon atom to which they are attached form cyclopropyl or cyclobutyl ring.