Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease
View Patent ↗Drug-Linker-Ligand Conjugates are disclosed in which a Drug is linked to a Ligand via a peptide-based Linker unit. In one embodiment, the Ligand is an Antibody. Drug-Linker compounds and Drug compounds are also disclosed. Methods for treating cancer, an autoimmune disease or an infectious disease using the compounds and compositions of the invention are also disclosed.
1. A drug-linker-antibody conjugate of Formula Ia:
or a pharmaceutically acceptable salt thereof, wherein,
L- is an antibody that binds to an antigen expressed on an activated human lymphocyte, wherein the activated human lymphocyte is associated with an autoimmune disease;
-A a -W w -Y y - is an enzymatically cleavable linker unit that links the Drug unit and the antibody, wherein:
-A- is a Stretcher unit;
a is 1;
each -W- is independently an Amino Acid unit;
-Y- is a self-immolative Spacer unit;
w is an integer ranging from 2 to 12,
y is 1 or 2;
p ranges from 1 to about 20; and
-D is a Drug unit of the formula
wherein, the wavy line indicates the point of attachment to the Spacer unit, and for each D:
R 2 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
R 3 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);
R 4 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) wherein R 5 is selected from the group consisting of —H and -methyl; or R 4 and R 5 join and form a ring with the carbon atom to which they are attached and R 4 and R 5 have the formula —(CR a R b ) n — wherein R a and R b are independently selected from the group consisting of —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle and n is selected from the group consisting of 2, 3, 4, 5 and 6;
R 6 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
R 7 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);
each R 8 is independently selected from the group consisting of —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);
R 9 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
R 10 is selected from the group consisting of:
Z is —O—, —S—,—NH—or —N(R 14 )—;
R 11 is selected from the group consisting of —H, —OH, —NH 2 , —NHR 14 , —N(R 14 ) 2 , —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle); or R 11 is an oxygen atom which forms a carbonyl unit (C═O) with the carbon atom to which it is attached and a hydrogen atom on this carbon atom is replaced by one of the bonds in the (C═O) double bond;
each R 12 is independently selected from the group consisting of -aryl and —C 3 -C 8 heterocycle;
R 13 is selected from the group consisting of —H, —OH, —NH 2 , —NHR 14 , —N(R 14 ) 2 , —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1-8 alkyl-(C 3 -C 8 heterocycle); and
each R 14 is independently —H or —C 1 -C 8 alkyl.
2. A drug-linker-antibody conjugate of the formula Ia:
or a pharmaceutically acceptable salt thereof, wherein,
L- is an antibody that binds to an antigen expressed on an activated human lymphocyte, wherein the activated human lymphocyte is associated with an autoimmune disease;
-A a -W w -Y y - is an enzymatically cleavable linker unit that links the Drug unit and the antibody, wherein:
-A- is a Stretcher unit;
a is 1;
each -W- is independently an Amino Acid unit;
-Y- is a self-immolative Spacer unit;
w is an integer ranging from 2 to 12;
y is 1 or 2;
p ranges from 1 to about 20; and
-D is a Drug unit having the structure
wherein, the wavy line indicates the point of attachment to the Spacer unit, and for each D:
R 2 is selected from the group consisting of —H and -methyl;
R 3 is selected from the group consisting of —H, -methyl, and -isopropyl;
R 4 is selected from the group consisting of —H and -methyl;
R 5 is selected from the group consisting of -isopropyl, -isobutyl, -sec-butyl, -methyl and -t-butyl or R 4 and R 5 join and form a ring with the carbon atom to which they are attached and R 4 and R 5 have the formula —(CR a R b ) n — where R a and R b are independently selected from the group consisting of —H, —C 1 -C 8 alkyl, and —C 3 -C 8 carbocycle, and n is selected from the group consisting of 2, 3, 4, 5 and 6;
R 6 is selected from the group consisting of —H and -methyl;
each R 8 is independently selected from the group consisting of —OH, -methoxy and -ethoxy;
R 10 is selected from the group consisting of:
R 24 is selected from the group consisting of H and —C(O)R 25 ; wherein R 25 is selected from the group consisting of —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);
Z is —O—, —NH—, —OC(O)—, —NHC(O)—, or —NR 28 C(O)—; where R 28 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
n is 0 or 1; and
R 27 is selected from the group consisting of —H, —N 3 , —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 - C 8 alkyl-(C 3 -C 8 heterocycle) when n is 0; and R 27 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) when n is 1.
3. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof wherein R 10 is
4. The drug-linker-antibody conjugate of claim 2 or a pharmaceutically acceptable salt thereof wherein R 10 is
5. The drug-linker-antibody conjugate of claim 3 or a pharmaceutically acceptable salt thereof wherein R 2 is —C 1 -C 8 alkyl.
6. The drug-linker-antibody conjugate of claim 4 or a pharmaceutically acceptable salt thereof wherein R 2 is methyl.
7. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof where -D is a Drug unit having the structure
8. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof wherein the antibody is a monoclonal antibody.
9. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof wherein the antibody is a full length immunoglobulin molecule.
10. The drug-linker-antibody conjugate of claim 8 or a pharmaceutically acceptable salt thereof wherein the antibody comprises a human immunoglobulin constant region.
11. The drug-linker-antibody conjugate of claim 10 or a pharmaceutically acceptable salt thereof wherein the antibody is an IgG 1.
12. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof where -W w - is -valine-citrulline-, the amino terminus of -W w - forming a bond with a Stretcher unit, and the C— terminus of -W w - forming a bond with a Spacer unit.
13. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof wherein p ranges from 1 to about 5.
14. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof wherein p ranges from 1 to 10.
15. The drug-linker-antibody conjugate of claim 1 or a pharmaceutically acceptable salt thereof wherein the linker unit is cleavable by cathepsin B.
16. The drug-linker-antibody conjugate of claim 1 having the formula below:
or a pharmaceutically acceptable salt thereof, where E is —CH 2 — or —CH 2 CH 2 O—; e is an integer ranging either from 0-10 when E is —CH 2 —, or from 1-10 when E is —CH 2 CH 2 —O—; F is —CH 2 —; f is 0 or 1; and p ranges from 1 to about 20.
17. The drug-linker-antibody conjugate of claim 16 or a pharmaceutically acceptable salt thereof wherein the antibody is a monoclonal antibody.
18. The drug-linker-antibody conjugate of claim 16 or a pharmaceutically acceptable salt thereof wherein the antibody is a full length immunoglobulin molecule.
19. The drug-linker-antibody conjugate of claim 17 or a pharmaceutically acceptable salt thereof wherein the antibody comprises a human immunoglobulin constant region.
20. The drug-linker-antibody conjugate of claim 19 or a pharmaceutically acceptable salt thereof wherein the antibody is an IgG1.
21. The drug-linker-antibody conjugate of claim 16 or a pharmaceutically acceptable salt thereof wherein p ranges from 1 to about 5.
22. The drug-linker-antibody conjugate of claim 16 or a pharmaceutically acceptable salt thereof wherein p ranges from 1 to 10.
23. The drug-linker-antibody conjugate of claim 1 having the formula below:
or a pharmaceutically acceptable salt thereof.
24. The drug-linker-antibody conjugate of claim 23 or a pharmaceutically acceptable salt thereof wherein the antibody is a monoclonal antibody.
25. The drug-linker-antibody conjugate of claim 23 or a pharmaceutically acceptable salt thereof wherein the antibody is full length immunoglobulin molecule.
26. A composition comprising drug-linker-antibody conjugates having Formula Ia:
or a pharmaceutically acceptable salt thereof;
wherein,
L- is an antibody that binds to an antigen expressed on an activated human lymphocyte, wherein the activated human lymphocyte is associated with an autoimmune disease;
-A a -W w -Y y - is an enzymatically cleavable linker unit that links the Drug unit and the antibody, wherein:
-A- is a Stretcher unit;
a is 1;
each -W- is independently an Amino Acid unit;
-Y- is a self-immolative Spacer unit;
w is an integer ranging from 2 to 12;
y is 1 or 2;
p ranges from 1 to 10 and is the average number of -A a -W w -Y y -D units per antibody in the composition; and
-D is a Drug unit of the formula
wherein, the wavy line indicates the point of attachment to the Spacer unit, and for each D:
R 2 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
R 3 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);
R 4 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) wherein R 5 is selected from the group consisting of —H and -methyl; or R 4 and R 5 join and form a ring with the carbon atom to which they are attached and R 4 and R 5 have the formula —(CR a R b ) n — wherein R a and R b are independently selected from the group consisting of —H, —C 1 -C 8 alkyl and —C 3 -C 8 carbocycle and n is selected from the group consisting of 2, 3, 4, 5 and 6;
R 6 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
R 7 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);
each R 8 is independently selected from the group consisting of —H, —OH, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle and —O—(C 1 -C 8 alkyl);
R 9 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
R 10 is selected from the group consisting of:
Z is —O—, —S—,—NH— or —N(R 14 )—;
R 11 is selected from the group consisting of —H, —OH, —NH 2 , —NHR 14 , —N(R 14 ) 2 , —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle); or R 11 is an oxygen atom which forms a carbonyl unit (C═O) with the carbon atom to which it is attached and a hydrogen atom on this carbon atom is replaced by one of the bonds in the (C═O) double bond;
each R 12 is independently selected from the group consisting of -aryl and —C 3 -C 8 heterocycle;
R 13 is selected from the group consisting of —H, —OH, —NH 2 , —NHR 14 , —N(R 14 ) 2, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, —O—(C 1 -C 8 alkyl), -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and —C 1-8 alkyl-(C 3 -C 8 heterocycle); and
each R 14 is independently —H or —C 1 -C 8 alkyl; and a pharmaceutically acceptable carrier or vehicle.
27. A composition comprising drug-linker-antibody conjugates having Formula Ia:
or a pharmaceutically acceptable salt thereof, wherein,
L- is an antibody that binds to an antigen expressed on an activated human lymphocyte, wherein the activated human lymphocyte is associated with an autoimmune disease;
-A a -W w -Y y - is an enzymatically cleavable linker unit that links the Drug unit and the antibody , wherein:
-A- is a Stretcher unit;
a is 1;
each -W- is independently an Amino Acid unit;
-Y- is a self-immolative Spacer unit;
w is an integer ranging from 2 to 12;
y is 1 or 2;
p ranges from 1 to 10 and is the average number of -A a -W w -Y y -D units per antibody in the composition; and
-D is a Drug unit having the structure
wherein, the wavy line indicates the point of attachment to the Spacer unit, and for each D:
R 2 is selected from the group consisting of —H and -methyl;
R 3 is selected from the group consisting of —H, -methyl, and -isopropyl;
R 4 is selected from the group consisting of —H and -methyl;
R 5 is selected from the group consisting of -isopropyl, -isobutyl, -sec-butyl, -methyl and -t-butyl or R 4 and R 5 join and form a ring with the carbon atom to which they are attached and R 4 and R 5 have the formula —(CR a R b ) n — where R a and R b are independently selected from the group consisting of —H, —C 1 -C 8 alkyl, and —C 3 -C 8 carbocycle, and n is selected from the group consisting of 2, 3, 4, 5 and 6;
R 6 is selected from the group consisting of —H and -methyl;
each R 8 is independently selected from the group consisting of —OH, -methoxy and -ethoxy;
R 10 is selected from the group consisting of:
R 24 is selected from the group consisting of H and —C(O)R 25 —; wherein R 25 is selected from the group consisting of —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);
Z is —O—, —NH—, —OC(O)—, —NHC(O)—, or —NR 28 C(O)—; where R 28 is selected from the group consisting of —H and —C 1 -C 8 alkyl;
n is 0 or 1; and
R 27 is selected from the group consisting of —H, —N 3 , —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-(C 3 -C 8 heterocycle) when n is 0; and
R 27 is selected from the group consisting of —H, —C 1 -C 8 alkyl, —C 3 -C 8 carbocycle, -aryl, —C 1 -C 8 alkyl-aryl, —C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), —C 3 -C 8 heterocycle and —C 1 -C 8 alkyl-( C 3 -C 8 heterocycle) when n is 1; and a pharmaceutically acceptable carrier or vehicle.
28. The composition of claim 26 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, R 2 is —C 1 -C 8 alkyl.
29. The composition of claim 27 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, R 2 is methyl.
30. The composition of claim 26 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, -D is a Drug unit having the structure
31. The composition of claim 26 wherein the drug-linker-antibody conjugates have the formula
or a pharmaceutically acceptable salt thereof, where E is —CH 2 — or —CH 2 CH 2 O—; e is an integer ranging either from 0-10 when E is —CH 2 —, or from 1-10 when E is —CH 2 CH 2 —O—; F is —CH 2 —; and f is 0 or 1.
32. The composition of claim 31 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody is a monoclonal antibody.
33. The composition of claim 31 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody is a full length immunoglobulin molecule.
34. The drug-linker-antibody conjugate of claim 32 or a pharmaceutically acceptable salt thereof wherein the antibody comprises a human immunoglobulin constant region.
35. The drug-linker-antibody conjugate of claim 34 or a pharmaceutically acceptable salt thereof wherein the antibody is an IgG 1.
36. The composition of claim 31 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, p ranges from 1 to about 5.
37. The composition of claim 26 wherein the drug-linker-antibody conjugates have the formula
or a pharmaceutically acceptable salt thereof.
38. The composition of claim 37 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody is a monoclonal antibody.
39. The composition of claim 37 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, the antibody is a full length immunoglobulin molecule.
40. The drug-linker-antibody conjugate of claim 38 or a pharmaceutically acceptable salt thereof wherein the antibody comprises a human immunoglobulin constant region.
41. The drug-linker-antibody conjugate of claim 40 or a pharmaceutically acceptable salt thereof wherein the antibody is an IgG1.
42. The composition of claim 37 wherein in the drug-linker-antibody conjugates or pharmaceutically acceptable salt thereof, p ranges from 1 to about 5.