Kits containing DLL3 antibody drug conjugates
Novel modulators, including antibodies and derivatives thereof, and methods of using such modulators to treat proliferative disorders are provided.
1. A kit for treating cancer comprising:
(a) one or more containers containing a composition comprising
an antibody drug conjugate of the formula M-[L-D]n, or a pharmaceutically acceptable salt thereof, wherein:
M comprises an anti-DLL3 antibody, wherein the anti-DLL3 antibody is
an internalizing antibody;
L comprises a linker;
D comprises a pyrrolobenzodiazepine (PBD); and
n is an integer from 1 to 20; and
(b) a label or package insert on or associated with the one or more containers indicating the composition is for treating cancer.
2. The kit of claim 1 , wherein the one or more containers is an intravenous solution bag, a vial, a bottle, or a syringe.
3. The kit of claim 1 , wherein the composition is provided as a lyophilized powder.
4. The kit of claim 3 , wherein the label or package insert indicate reconstitution of the lyophilized powder in sterile water or buffered saline.
5. The kit of claim 3 , wherein the lyophilized powder comprises one or more substances to inhibit protein aggregation.
6. The kit of claim 5 , wherein the one or more substances to inhibit protein aggregation is sucrose.
7. The kit of claim 1 , wherein the anti-DLL3 antibody specifically binds to an epitope within the DSL domain of a DLL3 protein set forth as SEQ ID NO: 3 or 4.
8. The kit of claim 1 , wherein the anti-DLL3 antibody specifically binds to an epitope comprising amino acids G203, R205 and P206 (SEQ ID NO: 10).
9. The kit of claim 1 , wherein the anti-DLL3 antibody is a chimeric antibody, a human antibody, a CDR-grafted antibody, or a humanized antibody.
10. The kit of claim 1 , wherein the anti-DLL3 antibody competes for binding to a human DLL3 protein with an antibody comprising a light chain variable region set forth as SEQ ID NO: 84 and a heavy chain variable region set forth as SEQ ID NO: 85.
11. The kit of claim 1 , wherein the anti-DLL3 antibody comprises:
(a) 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; or
(b) a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 212 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 213.
12. The kit of claim 1 wherein the antibody drug conjugate comprises the structure:
wherein:
CBA is a cell binding agent, which comprises the anti-DLL3 antibody M; and
A, L 1 , and L 2 are components of the linker L wherein:
A is a connecting group connecting L 1 to the cell binding agent (CBA);
L 1 is optionally a cleavable linker;
L 2 is a covalent bond or together with the —OC(═O)— group forms a self-immolative linker; and
wherein the linker L is attached to the pyrrolobenzodiazepine (PBD) at the position of the asterisk (*).
13. The kit of claim 12 , wherein L 1 comprises a cleavable linker and the cleavable linker comprises a dipeptide.
14. The kit of claim 13 , wherein the dipeptide is Phe-Lys, Val-Ala, Val-Lys, Ala-Lys, Val-Cit, Phe-Cit, Leu-Cit, Ile-Cit, Phe-Arg, or Trp-Cit.
15. The kit of claim 14 , wherein the dipeptide is Val-Ala.
16. The kit of claim 12 , wherein the moiety:
comprises the structure:
wherein the wavy line indicates the point of attachment of the structure directly to A or to a remaining portion of L1 that is further connected to A and the (*) indicates the point of attachment to the PBD.
17. The kit of claim 1 , wherein the pyrrolobenzodiazepine (PBD) comprises 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;
R 2 is selected from H, OH, ═O, ═CH 2 , CN, R, OR, ═CH—R D , ═C(R D ) 2 , O—SO 2 —R, CO 2 R, COR, and halo, where R D is selected from R, CO 2 R, COR, CHO, CO 2 H, and halo;
R 6 and R 9 are each independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo;
R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo;
R 10 is the linker L connected to the anti-DLL3 antibody;
Q is selected from O, S and NH;
R 11 is either H, or R or, where Q is O, SO 3 M, where M is a metal cation;
R and R′ are each independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 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;
X is selected from O, S, and N(H);
R 2″ , R 6″ , R 7″ , R 9″ , and X″ are as defined according to R 2 , R 6 , R 7 , R 9 , and X, respectively; and
R″ is a C 3-12 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.
18. The kit of claim 17 , wherein R 2 is R, wherein R is a C 5-20 aryl group.
19. The kit of claim 17 , wherein R 6 and R 9 are H.
20. The kit of claim 17 , wherein R 7 is OR.
21. The kit of claim 20 , wherein R is a C 1 alkyl.
22. The kit of claim 17 , wherein Q is O.
23. The kit of claim 22 , wherein R 11 is H.
24. The kit of claim 17 , wherein X and X″ are O.
25. The kit of claim 1 , wherein the label or package insert indicate that the composition is for treating lung cancer.
26. The kit of claim 25 , wherein the label or package insert indicate that the composition is for treating small cell lung cancer.
27. The kit of claim 1 , wherein the label or package insert indicate that the composition is for treating large cell neuroendocrine carcinoma.
28. The kit of claim 1 , wherein the label or package insert indicate that the composition is for treating thyroid cancer.
29. The kit of claim 1 , wherein the label or package insert indicate that that composition is for treating prostate cancer.
30. A kit for treating cancer comprising:
(a) one or more containers containing a composition comprising
a lyophilized antibody drug conjugate of the formula M-[L-D]n, or a pharmaceutically acceptable salt thereof, 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, and wherein the anti-DLL3 antibody is an internalizing antibody;
L comprises a linker;
D comprises a pyrrolobenzodiazepine (PBD) comprising 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;
R 2 is selected from H, OH, ═O, ═CH 2 , CN, R, OR, ═CH—R D , ═C(R D ) 2 , O—SO 2 —R, CO 2 R, COR, and halo, where R D is selected from R, CO 2 R, COR, CHO, CO 2 H, and halo;
R 6 and R 9 are each independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo;
R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo;
R 10 is the linker L connected to the anti-DLL3 antibody;
Q is selected from O, S and NH;
R 11 is either H, or R or, where Q is O, SO 3 M, where M is a metal cation;
R and R′ are each independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 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;
X is selected from O, S, and N(H);
R 2″ , R 6″ , R 7″ , R 9″ , and X″ are as defined according to R 2 , R 6 , R 7 , R 9 , and X, respectively; and
R″ is a C 3-12 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
n is an integer from 1 to 20; and
(b) a label or package insert on or associated with the one or more containers indicating the composition is for treating cancer.