Silvestrol antibody-drug conjugates and methods of use

An antibody drug conjugate compound comprising an antibody covalently attached through a linker to a silvestrol drug moiety, selected from Formulas Ia and Ib:

• or a pharmaceutically acceptable salt thereof,
• wherein
• Ra is a group selected from CH3O, CN, NO2, and Cl;
• L is a linker selected from the group consisting of:
• (i) a protease-cleavable, non-peptide linker having the formula;
• where Sir is a stretcher unit covalently attached to the antibody, Y is a spacer unit covalently attached to the silvestrol drug moiety, and PM is a peptidomimetic unit having the formula:
• -Str-PM-Y—
• where R7 and R8 together form a C3-C7 cycloalkyl ring, and AA is an amino acid side chain selected from H, —CH3, CH2(C6H5), —CH2CH2CH2CH2NH2, —CH2CH2CH2NHC(NH)NH2, —CH2CH(CH3)2, and —CH2CH2CH2NHC(O)NH2;
• and
• (ii) a peptide linker having the formula:
• -Str-PM-Y—
• where Str is a stretcher unit covalently attached to the antibody;
• Pep is a peptide of two to twelve amino acid residues, and Y is a spacer unit covalently attached to the silvestrol drug moiety;
• where for (i) and (ii) Str has the formula:
• where R6 is (CH2)5;
• where for (i) and (ii) Y comprises para-aminobenzyl or para-aminobenzyloxycarbonyl;
• p is an integer from 1 to 8;
• and
• Ab is an antibody which binds to one or more tumor-associated antigens or cell-surface receptors.