Monomethylvaline compounds capable of conjugation to ligands

Patent metadata

Field	Value
Publication number	US-10414826-B2
Application number	US-201715811190-A
Country	US
Kind code	B2
Filing date	Nov 13, 2017
Priority date	Nov 6, 2003
Publication date	Sep 17, 2019
Grant date	Sep 17, 2019

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 assay comprising:
(a) exposing cancer cells in vitro to an antibody drug conjugate having Formula Ia′:
Ab A a -W w —Y y -D) p   Ia′

or a pharmaceutically acceptable salt or solvate thereof, and

(b) determining the extent of binding of the antibody-drug conjugate to the cancer cells, and
(c) evaluating inhibition of the growth of the cancer cells,
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;
p ranges from 1 to about 20; and
D is a drug moiety of Formula D F :

wherein the wavy line of D F indicates the covalent attachment site to Y:
R 2 is selected from H and C 1 -C 8 alkyl;
R 3 is selected from H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);
R 4 is selected from H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);
R 5 is selected from H and methyl;
or R 4 and R 5 jointly form a carbocyclic ring and have the formula —(CR a R b ) n — wherein R a and R b are independently selected from H, C 1 -C 8 alkyl and C 3 -C 8 carbocycle and n is selected from 2, 3, 4, 5 and 6;
R 6 is selected from H and C 1 -C 8 alkyl;
R 7 is selected from H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);
each R 8 is independently selected from H, OH, C 1 -C 8 alkyl, C 3 -C 8 carbocycle and O-(C 1 -C 8 alkyl);
R 9 is selected from H and C 1 -C 8 alkyl;
R 10 is selected from aryl or C 3 -C 8 heterocycle;
Z is O, S, NH, or NR 12 , wherein R 12 is C 1 -C 8 alkyl;
R 11 is selected from H, C 1 -C 20 alkyl, aryl, C 3 -C 8 heterocycle, —(R 13 O) m —R 14 , or —(R 13 O) m —CH(R 15 ) 2 ;
m is an integer ranging from 1-1000;
R 13 is C 2 -C 8 alkyl;
R 14 is H or C 1 -C 8 alkyl;
each occurrence of R 15 is independently H, COOH, —(CH 2 ) n —N(R 16 ) 2 , —(CH 2 ) n SO 3 H, or —(CH 2 ) n —SO 3 —C 1 -C 8 alkyl;
each occurrence of R 16 is independently H, C 1 -C 8 alkyl, or —(CH 2 ) n —COOH; and
n is an integer ranging from 0 to 6.

2. The assay of claim 1 wherein the extent of binding is determined by immunohistochemistry (IHC).

3. The assay of claim 1 wherein the cells are breast tumor cells.

4. The assay of claim 1 , wherein the antibody-drug conjugate has the formula:

or a pharmaceutically acceptable salt thereof, wherein
R 17 is selected from the group consisting of C 1 -C 10 alkylene-, -C 3 -C 8 carbocyclo-, —O—(C 1 -C 8 alkyl)-, -arylene-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, -(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 3 -C 8 heterocyclo-, C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-, —(CH 2 CH 2 O) r —, and —(CH 2 CH 2 O) r —CH 2 —; and r is an integer ranging from 1-10.

5. The assay of claim 1 , wherein the antibody-drug conjugate has the formula:

or a pharmaceutically acceptable salt thereof.

6. The assay of claim 1 , wherein the antibody-drug conjugate has the formula:

or a pharmaceutically acceptable salt thereof.

7. The assay of claim 1 , wherein the antibody-drug conjugate has the formula:

or a pharmaceutically acceptable salt thereof.

8. The assay of claim 1 , wherein the antibody-drug conjugate has the formula:

or a pharmaceutically acceptable salt thereof.

9. The assay of claim 1 , wherein the antibody-drug conjugate has the formula:

or a pharmaceutically acceptable salt thereof.

10. The assay of claim 1 , wherein D has the formula:

or a pharmaceutically acceptable salt thereof.

11. The assay of claim 1 , wherein D has the formula:

or a pharmaceutically acceptable salt thereof.

12. The assay of claim 1 , wherein D has the formula:

or a pharmaceutically acceptable salt thereof.

13. The assay of claim 1 , wherein D has the formula:

or a pharmaceutically acceptable salt thereof.

14. The assay of claim 1 , wherein D has the formula:

or a pharmaceutically acceptable salt thereof.

15. The assay of claim 1 , wherein Z is —O— or —NH—.

16. The assay of claim 1 , wherein Z is —O— and R 11 is —H, methyl, or t-butyl.

17. The assay of claim 16 , wherein R 11 is —H.

18. The assay of claim 1 , wherein the antibody-drug conjugate has the formula selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, wherein Val is valine and Cit is citrulline.

19. The assay of claim 18 , wherein the antibody is a monoclonal antibody.

20. The assay of claim 1 , wherein the cancer cells overexpress at least one of CD30, CD40, CD70, and Lewis Y.

Assignees

• Seattle Genetics Inc

Inventors

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

Classifications

• A61P43/00

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/02

  specific for leukemia · CPC title