1-(chloromethyl)-2,3-dihydro-1h-benzo[e]indole dimer antibody-drug conjugate compounds, and methods of use and treatment

An antibody-drug conjugate compound having the formula:

• Ab-(L-D)p
• wherein:
• Ab is an antibody;
• L is a linker having the formula:
• -Str-(Pep)m-(Sp)n-
• where Str is a stretcher unit covalently attached to the antibody;
• Pep is an optional peptide unit of two to twelve amino acid residues, Sp is an optional spacer unit covalently attached to a dimer drug moiety, and m and n are independently selected from 0 and 1;
• p is an integer from 1 to 8;
• D is the dimer drug moiety having the formula:
• where
• R1 is selected from H, P(O)3H2, C(O)NRaRb, or a bond to L;
• R2 is selected from H, P(O)3H2, C(O)NRaRb, or a bond to L;
• Ra and Rb are independently selected from H and C1-C6 alkyl optionally substituted with one or more F,
• or Ra and Rb form a five or six membered heterocyclyl group;
• T is a tether group selected from C3-C12 alkylene, Y, (C1-C6 alkylene)-Y—(C1-C6 alkylene), (C1-C6 alkylene)-Y—(C1-C6 alkylene)-Y—(C1-C6 alkylene), (C2-C6 alkenylene)-Y—(C2-C6 alkenylene), and (C2-C6 alkynylene)-Y—(C2-C6 alkynylene);
• where Y is independently selected from O, S, NR1, aryl, and heteroaryl;
• where alkylene, alkenylene, aryl, and heteroaryl are independently and optionally substituted with F, OH, O(C1-C6 alkyl), NH2, NHCH3, N(CH3)2, OP(O)3H2, or C1-C6 alkyl, where alkyl is optionally substituted with one or more F;
• or alkylene, alkenylene, aryl, and heteroaryl are independently and optionally substituted with a bond to L;
• D′ is a drug moiety selected from:
• where the wavy line indicates the site of attachment to T;
• X1 and X2 are independently selected from O and NR3, where R3 is selected from H and C1-C6 alkyl optionally substituted with one or more F;
• R4 is H, CO2R, or a bond to L, where R is C1-C6 alkyl or benzyl;
• and
• R5 is H or C1-C6 alkyl;
• wherein the antibody binds to Napi2b and
• the antibody comprises three light chain hypervariable regions (HVR-L1, HVR-L2 and HVR-L3) and three heavy chain hypervariable regions (HVR-H1, HVR-H2 and HVR-H3) wherein:
• HVR-L1 comprises the amino acid sequence of SEQ ID NO:75;
• HVR-L2 comprises the amino acid sequence of SEQ ID NO:76;
• HVR-L3 comprises the amino acid sequence of SEQ ID NO:77.
• HVR-H1 comprises the amino acid sequence of SEQ ID NO:78;
• HVR-H2 comprises the amino acid sequence of SEQ ID NO:79;
• and
• HVR-H3 comprises the amino acid sequence of SEQ ID NO:80;
• or
• the antibody comprises a light chain hypervariable region comprising the amino acid sequence of SEQ ID NO:81 or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:82.