Methods of using monomethylvaline compositions having phenylalanine carboxy modifications at the C-terminus

Patent metadata

Field	Value
Publication number	US-9522194-B2
Application number	US-201414502210-A
Country	US
Kind code	B2
Filing date	Sep 30, 2014
Priority date	Jul 7, 2005
Publication date	Dec 20, 2016
Grant date	Dec 20, 2016

Abstract

Auristatin peptide analogs of MeVal-Val-Dil-Dap-Phe (MMAF) having a carboxylic acid equivalent at the C-terminal phenylalanine 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 in inhibiting cell proliferation and are represented by the general structure of

L v -[(LU) 0-1 -(D) 1-4 ] p

wherein L- is Ligand unit; LU is a Linker unit (LU); v is 1; p is an number ranging from about 1 to about 20; and D is a drug moiety having the formula:

wherein the moiety —N(R 9 )Z 1 is a phenylalanine bioisostere, wherein Z 1 is —CH(R 10 )Z 2 so that the phenylalanine bioisostere has the structure of Formula A:

and wherein the substituents R 2 -R 10 , X 1 and Z 2 are as defined.

First claim

What is claimed is:

1. A method for therapeutic treatment of cancer comprising administering to a patient in need thereof of an effective amount of an Antibody-Drug Conjugate composition wherein the composition is represented by the structure of Formula Ia′:
Ab-(A a -W w -Y y -D) p   Ia′

wherein
Ab is an antibody;
A is a Stretcher unit;
a is 0 or 1;
each W is independently an Amino Acid unit;
w is an integer ranging from 0 to 12;
Y is a Spacer unit;
y is 0, 1 or 2;
D is a drug moiety having Formula D:

wherein, independently for each D that is present:
R 2 is selected from the group consisting of H and C 1 -C 8 alkyl;
R 3 is C 1 -C 8 alkyl;
R 4 is C 1 -C 8 alkyl;
R 5 is selected from the group consisting of H and methyl;
R 6 is selected from the group consisting of H and C 1 -C 8 alkyl;
R 7 is selected from the group consisting of H and C 1 -C 8 alkyl
each R 8 is independently selected from the group consisting of H, OH, and O—(C 1 -C 8 alkyl);
and the moiety —N(R 9 )Z 1 is a phenylalanine bioisostere,
wherein Z 1 is —CH(R 10 )Z 2 so that the phenylalanine bioisostere has the structure of Formula A:

wherein R 9 is selected from the group consisting of H, C 1 -C 20 alkyl, C 3 -C 8 carbocyclyl, X 1 -aryl, X 1 -(C 3 -C 8 -carbocyclyl), X 1 -C 3 -C 8 -heterocyclyl and an amino protecting group;
R 10 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, CH 2 -(C 3 -C 8 carbocycle), CH 2 -aryl and CH 2 -C 3 -C 8 heterocycle; and
Z 2 is

wherein X 1 is independently C 1 -C 10 alkylene; and subscript p is a number ranging from 1 to about 20.

2. The method of claim 1 wherein the Antibody-Drug Conjugate composition is represented by the structure of:

wherein mAb is a monoclonal antibody (mAb);
S is a sulfur atom of the monoclonal antibody; and
Z is the phenylalanine bioisostere moiety of Formula A.

3. The method of claim 2 wherein R 9 of Formula A is selected from the group consisting of H, C 1 -C 20 alkyl, C 3 -C 8 carbocyclyl, X 1 -aryl, X 1 -(C 3 -C 8 -carbocyclyl) and X 1 -C 3 -C 8 -heterocyclyl.

4. The method of claim 2 , wherein R 9 of Formula A is H.

5. The method of claim 2 , wherein R 10 of Formula A is benzyl.

6. The method of claim 1 wherein the antibody is selected from AC10, S2C6, BR96, 1F5, 1F6, M195 and 2F2.

7. The method of claim 1 wherein the patient is a human.

8. The method of claim 1 , further comprising administering an effective amount of an additional anticancer agent.

9. The method of claim 1 wherein the amount of the Antibody-Drug Conjugate composition administered to the patient is in the range of about 0.1 to about 10 mg/kg of patient weight, wherein the administered Antibody-Drug Conjugate composition is in a pharmaceutically acceptable formulation.

10. The method of claim 9 wherein said formulation of the Antibody-Drug Conjugate composition is administered at about three week intervals.

11. The method of claim 9 wherein said formulation of the Antibody-Drug Conjugate composition is administered parenterally or intravenously.

12. The method of claim 1 wherein the Antibody-Drug Conjugate composition is represented by the structure of:

wherein mAb is a monoclonal antibody (mAb); and
S is a sulfur atom of the monoclonal antibody.

Assignees

• Seattle Genetics Inc

Inventors

• Doronina Svetlana O
• Kline Toni Beth
• Jeffrey Scott
• Senter Peter D
• Meyer Damon

Classifications

• A61K47/6811

  the drug being a protein or peptide, e.g. transferrin or bleomycin · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K7/02

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

• A61K39/3955 Primary

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• C07K5/0205 Primary

  containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof · CPC title