Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease
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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.
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Citations
159 Claims
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1-119. -119. (canceled)
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120. A compound of the Formula Ia:
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L
Aa-Ww-Yy-D)p
Iaor a pharmaceutically acceptable salt or solvate thereof wherein, L- is a chimeric AC10 antibody; -A- is a Stretcher unit; a is 1; each -W- is independently an Amino Acid unit; -Y- is a 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 independently at each location; R2 is selected from —
H and —
C1-C8 alkyl;R3 is selected from —
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 —
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 —
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 —
H, —
C1-C8 alkyl and —
C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6;R6 is selected from —
H and —
C1-C8 alkyl;R7 is selected from —
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 R5 is independently selected from —
H, —
OH, —
C1-C8 alkyl, —
C3-C8 carbocycle and —
O—
(C1-C8 alkyl);R9 is selected from —
H and —
C1-C8 alkyl;R10 is wherein the wavy line indicates the point of attachment to the rest or the Drug unit; R11 is selected from —
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 -aryl and —
C3-C8 heterocycle;R13 is selected from —
H, —
OH, —
NH2, —
NHR14, —
N(R14)2, —
C1-C9 alkyl, —
C3-C8 carbocycle, —
O—
(C1-C8 alkyl), -aryl, —
C1-C9 alkyl-aryl, —
C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and —
C1-8 alkyl-(C3-C8 heterocycle); andeach R14 is independently —
H or —
C1-C8 alkyl.- View Dependent Claims (122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135)
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123. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 120 where -Y- is a self-immolative spacer.
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124. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 120 where —
- Yy—
isQ is selected from —
C1-C8 alkyl, —
O—
(C1-C8 alkyl), -halogen, -nitro and -cyano; and
m is an integer ranging from 0-4, the amino terminus of —
Yy—
forming a bond with the Amino acid unit and the carboxyl terminus of —
Yy—
forming a bond with the Drug unit.
- Yy—
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125. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 120 where -A- is
wherein R17 is — - C1-C10 alkylene, C3-C8 carbocyclo-, —
O—
(C1-C8 alkyl)-, -arylene-, —
C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, —
C1-C10 alkylene-(C3-C8 carbocyclo)-, —
(C3-C8 carbocyclo)-C1-C10 alkylene-, —
C3-C8 heterocyclo-, —
C1-C10 alkylene-(C3-C8 heterocyclo)-, —
(C3-C8 heterocyclo)-C1-C10 alkylene-, —
(CH2CH2O)r—
, and —
(CH2CH2O)r—
CH2—
; and
r is an integer ranging from 1-10.
- C1-C10 alkylene, C3-C8 carbocyclo-, —
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126. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 120 where -A- is
and r is an integer ranging from 1-10, the carbonyl terminus of -A- forming a bond with the Amino acid unit and the succinimido terminus of -A- forming a bond with the antibody. -
127. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 126 where -A- is
the carbonyl terminus of -A- forming a bond with the Amino acid unit and the succinimido terminus of -A- forming a bond with the antibody. -
128. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 120 where —
- Ww—
is -Valine-Citrulline.
- Ww—
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129. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 120 wherein p ranges from 1 to about 5.
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130. The compound of claim 120 having the formula:
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or a pharmaceutically acceptable salt or solvate thereof.
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131. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 130 wherein p ranges from 1 to about 5.
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132. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 131 wherein the antibody is attached to the drug moiety through a sulfur atom of the antibody.
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133. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 132 wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.
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134. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 131 wherein the chimeric AC10 antibody comprises a human immunoglobulin IgG1 constant region.
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135. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 133 wherein the chimeric AC10 antibody comprises a human immunoglobulin IgG1 constant region.
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121. A compound of the formula Ia:
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L
Aa-Ww-Yy-D)p
Iaor a pharmaceutically acceptable salt or solvate thereof L- is a chimeric AC10 antibody; -A- is a Stretcher unit; a is 1; each -W- is independently an Amino Acid unit; -Y- is a 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 independently at each location; R2 is selected from —
H and -methyl;R3 is selected from —
H, -methyl, and -isopropyl;R4 is selected from —
H and -methyl;
R5 is selected from -isopropyl, -isobutyl, -sec butyl, -methyl and -t butyl or R4 and R5 join, have the formula—
(CRaRb)n—
where Ra and Rb are independently selected from —
H, —
C1-C8 alkyl, and —
C3-C8 carbocycle, and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;R6 is selected from —
H and -methyl;each R8 is independently selected from —
OH, -methoxy and -ethoxy;R10 is wherein the wavy line indicates the point of attachment to the rest of the Drug unit; and R24 is selected from H and —
C(O)R25—
;
wherein R25 is selected from —
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).
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136. A composition comprising drug-linker-ligand conjugates having Formula Ia:
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L
Aa-Ww-Yy-D)p
Iaor a pharmaceutically acceptable salt or solvate thereof; wherein, L- is a chimeric AC10 antibody; -A- is a Stretcher unit; a is 1; each -W- is independently an Amino Acid unit;
-Y- is a Spacer unit;w is an integer ranging from 2 to 12; y is 1 or 2; p ranges from 1 to about 20 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 independently at each location; R2 is selected from —
H and —
C1-C8 alkyl;R3 is selected from —
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 —
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 —
H and -methyl;
or R4 and R5 join, have the formula —
(CRaRb)n—
wherein Ra and Rb are independently selected from —
H, —
C1-C8 alkyl and —
C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;R6 is selected from —
H and —
C1-C8 alkyl;R7 is selected from —
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 —
H, —
OH, —
C1-C8 alkyl, —
C3-C8 carbocycle and —
O—
(C1-C8 alkyl);R9 is selected from —
H and —
C1-C8 alkyl;R10 is wherein the wavy line indicates the point of attachment to the rest of the Drug unit;
R11 is selected from —
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 -aryl and —
C3-C8 heterocycle;R13 is selected from —
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); andEach R14 is independently —
H or —
C1-C8 alkyl.- View Dependent Claims (138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159)
or a pharmaceutically acceptable salt or solvate thereof.
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142. The composition of claim 141 wherein p ranges from 1 to about 5.
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143. The composition of claim 141 wherein p ranges from about 3 to about 5.
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144. The composition of claim 141 wherein p ranges from about 2 to about 4.
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145. The composition of claim 141 wherein p is about 4.
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146. The composition of claim 142 wherein the antibody is attached to the drug moiety through a sulfur atom of the antibody.
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147. The composition of claim 144 wherein the antibody is attached to the drug moiety through a sulfur atom of the antibody.
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148. The composition of claim 145 wherein the antibody is attached to the drug moiety through a sulfur atom of the antibody.
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149. The composition of claim 146 wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.
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150. The composition of claim 147 wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.
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151. The composition of claim 148 wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.
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152. The composition of claim 141 wherein the chimeric AC10 antibody comprises a human immunoglobulin IgG1 constant region.
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153. The composition of claim 145 further comprising a pharmaceutically acceptable carrier.
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154. The composition of claim 144 wherein the chimeric AC10 antibody comprises a human immunoglobulin IgG1 constant region.
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155. A method for the treatment of a cancer expressing the CD30 antigen or an autoimmune disease comprising administering to an animal in need thereof an effective amount of a composition of claim 136.
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156. The method of claim 155 wherein the drug-linker-ligand conjugates have the formula:
or a pharmaceutically acceptable salt or solvate thereof, wherein p ranges from 1 to 5.
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157. The method of claim 156 wherein p is about 4.
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158. The method of claim 156 for the treatment of cancer wherein the cancer is Hodgkin'"'"'s Disease or anaplastic large cell lymphoma.
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159. The method of claim 157 for the treatment of cancer wherein the cancer is Hodgkin'"'"'s Disease or anaplastic large cell lymphoma.
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137. A composition comprising drug-linker-ligand conjugates having Formula Ia:
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L
Aa-Ww-Yy-D)p
Iaor a pharmaceutically acceptable salt or solvate thereof L- is a chimeric AC10 antibody; -A- is a Stretcher unit; a is 1; each -W- is independently an Amino Acid unit; -Y- is a Spacer unit; w is an integer ranging from 2 to 12; y is 1 or 2; p ranges from 1 to about 20 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 independently at each location; R2 is selected from —
H and -methyl;R3 is selected from —
H, -methyl, and -isopropyl;R4 is selected from —
H and -methyl;
R5 is selected from -isopropyl, -isobutyl, -sec-butyl, -methyl and -t butyl or R4 and R5 join, have the formula —
(CRaRb)n—
where Ra and Rb are independently selected from —
H, —
C1-C8 alkyl, and —
C3-C8 carbocycle, and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;R6 is selected from —
H and -methyl;each R8 is independently selected from —
OH, -methoxy and -ethoxy;R10 is wherein the wavy line indicates the point of attachment to the rest of the Drug unit; and
R24 is selected from H and —
C(O)R25—
;
wherein R25 is selected from —
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).
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Specification