Methods of using monomethylvaline compositions having phenylalanine carboxy modifications at the C-terminus
View Patent ↗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.
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.