Monomethylvaline compounds capable of conjugation to ligands
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:
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.