Dll3 modulators and methods of use

A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-DLL3 antibody drug conjugate (ADC), or a pharmaceutically acceptable salt thereof, wherein the antibody drug conjugate (ADC) comprises the formula M-[L-D]n, wherein:

• M comprises an anti-DLL3 antibody;
• L comprises a linker;
• D comprises a pyrrolobenzodiazepine (PBD);
• and
• n is an integer from about 1 to about 20.

A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-DLL3 antibody drug conjugate (ADC), or a pharmaceutically acceptable salt thereof, wherein the antibody drug conjugate (ADC) comprises the formula M-[L-D]n, wherein:

• M comprises an anti-DLL3 antibody that specifically binds to an epitope within the DSL domain of a DLL3 protein set forth as SEQ ID NO:
• 3 or 4;
• L comprises an optional linker;
• D comprises a cytotoxic agent;
• and
• n is an integer from about 1 to about 20.

A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-DLL3 antibody drug conjugate (ADC), or a pharmaceutically acceptable salt thereof, wherein the antibody drug conjugate (ADC) comprises the formula M-[L-D]n, wherein:

• M comprises an anti-DLL3 antibody comprising residues 24-34 of SEQ ID NO:
• 84 for CDR-L1, residues 50-56 of SEQ ID NO:
• 84 for CDR-L2, residues 89-97 of SEQ ID NO:
• 84 for CDR-L3, residues 31-35 of SEQ ID NO:
• 85 for CDR-H1, residues 50-65 of SEQ ID NO:
• 85 for CDR-H2 and residues 95-102 of SEQ ID NO:
• 85 for CDR-H3, wherein the residues are numbered according to Kabat;
• L comprises a linker;
• D comprises a pyrrolobenzodiazepine (PBD) the formula AC:
• wherein:
• the dotted lines indicate the optional presence of a double bond, and wherein only one of the dotted lines in a given ring can be a double bond;
• R2 is selected from H, OH, ═O, ═CH2, CN, R, OR, ═CH—RD, ═C(RD)2, O—SO2—R, CO2R, COR, and halo, where RD is selected from R, CO2R, COR, CHO, CO2H, and halo;
• R6 and R9 are each independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, Me3Sn and halo;
• R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, Me3Sn and halo;
• R10 is a linker connected to a modulator or fragment or derivative thereof;
• Q is selected from O, S and NH;
• R11 is selected from H and R, or if Q is O, then R11 is SO3M, where M is a metal cation;
• R and R′ are each independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups, and optionally in relation to the group NRR′, R and R′ together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring;
• R2″, R6″, R7″, R9″ and X″ are as defined according to R2, R6, R7, R9, and X, respectively;
• R″ is a C3-12 alkylene group, which comprises a chain optionally interrupted by one or more heteroatoms, one or more rings, or both one or more heteroatoms and one or more rings, wherein the optional one or more rings are optionally substituted;
• and
• X is selected from O, S, and N(H);
• and
• n is an integer from about 1 to about 20

A method of treating small cell lung cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-DLL3 antibody drug conjugate (ADC), or a pharmaceutically acceptable salt thereof, wherein the antibody drug conjugate (ADC) comprises the formula M-[L-D]n, wherein:

• M comprises an anti-DLL3 antibody that specifically binds to an epitope within the DSL domain of a DLL3 protein set forth as SEQ ID NO:
• 3 or 4;
• L comprises a linker;
• D comprises a pyrrolobenzodiazepine (PBD);
• and
• n is an integer from about 1 to about 20.