Silvestrol antibody-drug conjugates and methods of use

• US 10,639,378 B2
• Filed: 06/05/2017
• Issued: 05/05/2020
• Est. Priority Date: 06/06/2016
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Pillow, Thomas, Polson, Andrew G., Zheng, Bing
• Primary Examiner(s): Barsky, Jared
• Application Number:
  US15/613,477
• Publication Number:
  US 20170348422A1
• Time in Patent Office: 1,065 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/572 cytotoxic response
• CPC Class Codes: A61K 2039/627 characterised by the linker
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/541 Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6855 the tumour determinant being from breast cancer cell
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07K 19/00 Hybrid peptides , i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
• CPC Class Codes: G01N 33/567 utilising isolate of tissue or organ as binding agent

Abstract

The invention relates generally to a silvestrol molecule activated with a leaving group. The invention further relates generally to an antibody-drug conjugate comprising an antibody conjugated by a linker to one or more silvestrol drug moieties and methods of treatment.

Claims

1. A silvestrol-linker intermediate compound of Formula II:

2. The silvestrol-linker intermediate compound of claim 1 wherein L is a protease-cleavable, non-peptide linker having the formula:

-Str-PM-Y—

3. The silvestrol-linker intermediate compound of claim 2 wherein Str is (CH₂)₅.

4. The silvestrol-linker intermediate compound of claim 2 wherein PM has the formula:

5. The silvestrol-linker intermediate compound of claim 4 wherein R⁷ and R⁸ together form cyclobutyl.

6. A silvestrol-linker intermediate compound selected from:

7. The silvestrol-linker intermediate compound of claim 6 having the structure: