Monomethylvaline compounds capable of conjugation to ligands
View Patent ↗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.
1. An antibody-drug conjugate having the formula IIIa:
or a pharmaceutically acceptable salt thereof, wherein:
Ab is an antibody that specifically binds to the CD19 antigen
R 17 is selected from the group consisting of C 1 -C 10 alkylene-, —C 3 -C 8 carbocyclo-, —O—(C 1 -C 8 -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 —;
r is an integer ranging from 1-10;
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 C(O) in formula IIIa, independently at each location:
R 2 is selected from the group consisting of H and C 1 -C 8 alkyl;
R 3 is selected from the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of H, C 1 -C 8 alkyl and C 3 -C 8 carbocycle and n is selected from the group consisting of 2, 3, 4, 5 and 6;
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, 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 the group consisting of H, OH, C 1 -C 8 alkyl, C 3 -C 8 carbocycle and O—(C 1 -C 8 alkyl);
R 9 is selected from the group consisting of 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 antibody-drug conjugate of claim 1 , wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.
3. The antibody-drug conjugate of claim 2 , wherein p is 2 to 5.
4. The antibody-drug conjugate of claim 1 , wherein p is 2 to 8.
5. The antibody-drug conjugate of claim 1 , wherein p is 2 to 5.
6. The antibody-drug conjugate of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
7. The antibody-drug conjugate of claim 6 , wherein p is 2 to 4 and D has the formula:
or a pharmaceutically acceptable salt thereof.
8. The antibody-drug conjugate of claim 1 , wherein D has the formula:
or a pharmaceutically acceptable salt thereof.
9. The antibody-drug conjugate of claim 1 , wherein D has the formula:
or a pharmaceutically acceptable salt thereof.
10. The antibody-drug conjugate of claim 1 , wherein D has the formula:
or a pharmaceutically acceptable salt thereof.
11. The antibody-drug conjugate of claim 1 , wherein D has the formula:
or a pharmaceutically acceptable salt thereof.
12. The antibody-drug conjugate of claim 1 , wherein D has the formula:
or a pharmaceutically acceptable salt thereof.
13. The antibody-drug conjugate of claim 1 , wherein the antibody is a monoclonal antibody.
14. An antibody-drug conjugate of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising an effective amount of the antibody-drug conjugate of claim 1 and a pharmaceutically acceptable diluent, carrier or excipient.