Pyrrolobenzodiazepine antibody drug conjugates and methods of use
The invention provides antibody-drug conjugates comprising an antibody conjugated to a pyrrolobenzodiazepine drug moiety via a disulfide linker, pyrrolobenzodiazepine linker-drug intermediates, and methods of using the antibody-drug conjugates.
1. A linker-drug intermediate of Formula I:
wherein X -- Y is selected from the group consisting of CH 2 —CH 2 , CH═CH, C(═O)NH, and CH 2 —NH;
A is a 5-membered or 6-membered heterocyclic ring, optionally substituted with F, C 1 -C 6 alkyl, or ═C(R) 2 where R is independently H, F, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
R 1 and R 2 are independently selected from the group consisting of H and C 1 -C 6 alkyl, or R 1 and R 2 form a 3, 4, 5, or 6-membered cycloalkyl or heterocyclyl group;
each R 3 is independently selected from the group consisting of NO 2 , Cl, F, CN, CO 2 H and Br; and
m is 1 or 2.
2. The linker-drug intermediate of claim 1 of Formula Ia:
3. The linker-drug intermediate of claim 1 of Formula Ib:
4. The linker-drug intermediate of claim 1 having Formula Ic:
wherein R 4 and R 5 are each H, or R 4 and R 5 are ═O.
5. The linker-drug intermediate of claim 1 of Formula Id:
wherein R 4 and R 5 are each H, or R 4 and R 5 are ═O.
6. The linker-drug intermediate of claim 5 wherein R 4 and R 5 are each H.
7. The linker-drug intermediate of claim 1 of Formula Ie:
8. The linker-drug intermediate of claim 1 wherein X -- Y is C(═O)—NH.
9. The linker-drug intermediate of claim 1 of Formula If:
10. The linker-drug intermediate of claim 1 wherein R 1 and R 2 along with the carbon atom to which they are attached form cyclopropyl or cyclobutyl ring.