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US 7,851,437 B2Granted
Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease
AssigneeSeattle Genetics, Inc.
InventorsPeter D. Senter, Svetlana O. Doronina, Brian E. Toki
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Abstract
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.
Claims42
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;
- -Aa-Ww-Yy- 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:
- R2 is selected from the group consisting of —H and —C1-C8 alkyl;
- R3 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- R4 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from the group consisting of —H and -methyl;
- or R4 and R5 join and form a ring with the carbon atom to which they are attached and R4 and R5 have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from the group consisting of —H, —C1-C8 alkyl and —C3-C8 carbocycle and n is selected from the group consisting of 2, 3, 4, 5 and 6;
- R6 is selected from the group consisting of —H and —C1-C8 alkyl;
- R7 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- each R8 is independently selected from the group consisting of —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R9 is selected from the group consisting of —H and —C1-C8 alkyl;
- R10 is selected from the group consisting of:
- Z is —O—, —S—,—NH—or —N(R14)—;
- R11 is selected from the group consisting of —H, —OH, —NH2, —NHR14, —N(R14)2, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- or R11 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 R12 is independently selected from the group consisting of -aryl and —C3-C8 heterocycle;
- R13 is selected from the group consisting of —H, —OH, —NH2, —NHR14, —N(R14)2, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-8 alkyl-(C3-C8 heterocycle);
- and
- each R14 is independently —H or —C1-C8 alkyl.
26 more elements
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;
- -Aa-Ww-Yy- 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:
- R2 is selected from the group consisting of —H and -methyl;
- R3 is selected from the group consisting of —H, -methyl, and -isopropyl;
- R4 is selected from the group consisting of —H and -methyl;
- R5 is selected from the group consisting of -isopropyl, -isobutyl, -sec-butyl, -methyl and -t-butyl or R4 and R5 join and form a ring with the carbon atom to which they are attached and R4 and R5 have the formula —(CRaRb)n— where Ra and Rb are independently selected from the group consisting of —H, —C1-C8 alkyl, and —C3-C8 carbocycle, and n is selected from the group consisting of 2, 3, 4, 5 and 6;
- R6 is selected from the group consisting of —H and -methyl;
- each R8 is independently selected from the group consisting of —OH, -methoxy and -ethoxy;
- R10 is selected from the group consisting of:
- R24 is selected from the group consisting of H and —C(O)R25;
- wherein R25 is selected from the group consisting of —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- Z is —O—, —NH—, —OC(O)—, —NHC(O)—, or —NR28C(O)—;
- where R28 is selected from the group consisting of —H and —C1-C8 alkyl;
- n is 0 or 1;
- and
- R27 is selected from the group consisting of —H, —N3, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1- C8 alkyl-(C3-C8 heterocycle) when n is 0;
- and R27 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) when n is 1.
25 more elements
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;
- -Aa-Ww-Yy- 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 -Aa-Ww-Yy-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:
- R2 is selected from the group consisting of —H and —C1-C8 alkyl;
- R3 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- R4 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from the group consisting of —H and -methyl;
- or R4 and R5 join and form a ring with the carbon atom to which they are attached and R4 and R5 have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from the group consisting of —H, —C1-C8 alkyl and —C3-C8 carbocycle and n is selected from the group consisting of 2, 3, 4, 5 and 6;
- R6 is selected from the group consisting of —H and —C1-C8 alkyl;
- R7 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- each R8 is independently selected from the group consisting of —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
- R9 is selected from the group consisting of —H and —C1-C8 alkyl;
- R10 is selected from the group consisting of:
- Z is —O—, —S—,—NH— or —N(R14)—;
- R11 is selected from the group consisting of —H, —OH, —NH2, —NHR14, —N(R14)2, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- or R11 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 R12 is independently selected from the group consisting of -aryl and —C3-C8 heterocycle;
- R13 is selected from the group consisting of —H, —OH, —NH2, —NHR14, —N(R14)2, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and —C1-8 alkyl-(C3-C8 heterocycle);
- and
- each R14 is independently —H or —C1-C8 alkyl;
- and a pharmaceutically acceptable carrier or vehicle.
28 more elements
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;
- -Aa-Ww-Yy- 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 -Aa-Ww-Yy-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:
- R2 is selected from the group consisting of —H and -methyl;
- R3 is selected from the group consisting of —H, -methyl, and -isopropyl;
- R4 is selected from the group consisting of —H and -methyl;
- R5 is selected from the group consisting of -isopropyl, -isobutyl, -sec-butyl, -methyl and -t-butyl or R4 and R5 join and form a ring with the carbon atom to which they are attached and R4 and R5 have the formula —(CRaRb)n— where Ra and Rb are independently selected from the group consisting of —H, —C1-C8 alkyl, and —C3-C8 carbocycle, and n is selected from the group consisting of 2, 3, 4, 5 and 6;
- R6 is selected from the group consisting of —H and -methyl;
- each R8 is independently selected from the group consisting of —OH, -methoxy and -ethoxy;
- R10 is selected from the group consisting of:
- R24 is selected from the group consisting of H and —C(O)R25—;
- wherein R25 is selected from the group consisting of —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1 -C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
- Z is —O—, —NH—, —OC(O)—, —NHC(O)—, or —NR28C(O)—;
- where R28 is selected from the group consisting of —H and —C1-C8 alkyl;
- n is 0 or 1;
- and
- R27 is selected from the group consisting of —H, —N3, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8alkyl-(C3-C8 heterocycle) when n is 0;
- and
- R27 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-( C3-C8 heterocycle) when n is 1;
- and a pharmaceutically acceptable carrier or vehicle.
27 more elements
Dependencies are inferred from the claim text.