Monomethylvaline compounds capable of conjugation to ligands

Patent metadata

Field	Value
Publication number	US-10808039-B2
Application number	US-201916507839-A
Country	US
Kind code	B2
Filing date	Jul 10, 2019
Priority date	Nov 6, 2003
Publication date	Oct 20, 2020
Grant date	Oct 20, 2020

Abstract

Auristatin peptides, including MeVal-Val-Dil-Dap-Norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), were prepared and attached to Ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.

First claim

What is claimed is:

1. An antibody-drug conjugate having the formula:

or a pharmaceutically acceptable salt thereof, wherein:
Ab is an antibody,
S is sulfur,
each —W w — unit is a tetrapeptide; wherein each —W— unit is independently an Amino Acid unit having the formula denoted below in the square bracket:

 wherein R 19 is hydrogen or benzyl,
Y is a Spacer unit,
y is 0, 1 or 2,
D is a drug moiety, and
p ranges from 1 to about 20,
wherein the S is a sulfur atom on a cysteine residue of the antibody, and
wherein the drug moiety is intracellularly cleaved in a patient from the antibody of the antibody-drug conjugate or an intracellular metabolite of the antibody-drug conjugate.

2. The antibody-drug conjugate of claim 1 , wherein Y is a self-immolative spacer.

3. The antibody-drug conjugate of claim 2 , wherein y is 1.

4. The antibody-drug conjugate of claim 3 , wherein p is about 3 to about 8.

5. The antibody-drug conjugate of claim 4 , wherein p is about 8.

6. The antibody-drug conjugate of claim 1 , 2 , 3 , 4 , or 5 , wherein the bioavailability of the antibody-drug conjugate or an intracellular metabolite of the antibody-drug conjugate in a patient is improved when compared to a drug compound comprising the drug moiety of the antibody-drug conjugate.

7. The antibody-drug conjugate compound of claim 1 , 2 , 3 , 4 , or 5 , wherein the bioavailability of the antibody-drug conjugate or an intracellular metabolite of the antibody-drug conjugate in a patient is improved when compared to an analog of the antibody-drug conjugate not having the drug moiety.

8. The antibody-drug conjugate compound of claim 1 , 2 , 3 , 4 , or 5 , wherein the drug moiety is intracellularly cleaved in a patient from an intracellular metabolite of the antibody-drug conjugate.

9. The antibody-drug conjugate of claim 1 , 2 , 3 , 4 , or 5 , wherein the antibody is a monoclonal antibody.

10. The antibody-drug conjugate of claim 9 , wherein the antibody is a humanized monoclonal antibody.

Assignees

• Seattle Genetics Inc

Inventors

• Doronina Svetlana O
• Senter Peter D
• Toki Brian E
• Kline Toni Beth

Classifications

• C07K16/32 Primary

  against translation products of oncogenes · CPC title

• A61K47/68031

  the drug being an auristatin · CPC title

• C07K7/02 Primary

  Linear peptides containing at least one abnormal peptide link · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• A61K2039/505

  comprising antibodies · CPC title