Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease

• US 20090324621A1
• Filed: 03/20/2009
• Published: 12/31/2009
• Est. Priority Date: 07/31/2002
• Status: Active Grant

• Current Assignee: Seagen Inc. (Pfizer Inc.)
• Original Assignee: Seattle Genetics Incorporated (Pfizer Inc.)
• Inventors: Doronina, Svetlana O., Senter, Peter D., Toki, Brian E.
• Granted Patent: US 7,829,531 B2
• Time in Patent Office: Days
• US Class Current: 424/181.1
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/642 the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
• CPC Class Codes: A61K 47/6817 Toxins
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6867 the tumour determinant being from a cell of a blood cancer
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 5/0205 containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof

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.

Claims

1-119. -119. (canceled)

120. A compound of the Formula Ia:

L

A_a-W_w-Y_y-D)_p 

 

Ia

or 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 —

(CR^aR^b)_n—

wherein R^a and R^b 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 —

C_1-8 alkyl-(C₃-C₈ heterocycle); and

each R¹⁴ is independently —

H or —

C₁-C₈ alkyl.

122. A compound or a pharmaceutically acceptable salt or solvate of the compound of claim 120 where -D is a Drug unit having the structure

123. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 120 where -Y- is a self-immolative spacer.

124. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 120 where —

Y_y—

is

Q 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 —

Y_y—

forming a bond with the Amino acid unit and the carboxyl terminus of —

Y_y—

forming a bond with the Drug unit.

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.

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 —

W_w—

is -Valine-Citrulline.

129. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 120 wherein p ranges from 1 to about 5.

130. The compound of claim 120 having the formula:

or a pharmaceutically acceptable salt or solvate thereof.

131. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 130 wherein p ranges from 1 to about 5.

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.

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.

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.

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.

121. A compound of the formula Ia:

L

A_a-W_w-Y_y-D)_p 

 

Ia

or 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—

(CR^aR^b)_n—

where R^a and R^b 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).

136. A composition comprising drug-linker-ligand conjugates having Formula Ia:

L

A_a-W_w-Y_y-D)_p 

 

Ia

or 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 -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 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 —

(CR^aR^b)ⁿ—

wherein R^a and R^b 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 —

C_1-8 alkyl-(C₃-C₈ heterocycle); and

Each R¹⁴ is independently —

H or —

C₁-C₈ alkyl.

138. The composition of claim 136 wherein p ranges from 1 to about 5.

139. The composition of claim 136 wherein p is about 4.

140. The composition of claim 136 further comprising a pharmaceutically acceptable carrier.

141. The composition of claim 136 wherein the drug-linker-ligand conjugates have the formula:

or a pharmaceutically acceptable salt or solvate thereof.

142. The composition of claim 141 wherein p ranges from 1 to about 5.

143. The composition of claim 141 wherein p ranges from about 3 to about 5.

144. The composition of claim 141 wherein p ranges from about 2 to about 4.

145. The composition of claim 141 wherein p is about 4.

146. The composition of claim 142 wherein the antibody is attached to the drug moiety through a sulfur atom of the antibody.

147. The composition of claim 144 wherein the antibody is attached to the drug moiety through a sulfur atom of the antibody.

148. The composition of claim 145 wherein the antibody is attached to the drug moiety through a sulfur atom of the antibody.

149. The composition of claim 146 wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.

150. The composition of claim 147 wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.

151. The composition of claim 148 wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.

152. The composition of claim 141 wherein the chimeric AC10 antibody comprises a human immunoglobulin IgG1 constant region.

153. The composition of claim 145 further comprising a pharmaceutically acceptable carrier.

154. The composition of claim 144 wherein the chimeric AC10 antibody comprises a human immunoglobulin IgG1 constant region.

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.

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.

157. The method of claim 156 wherein p is about 4.

158. The method of claim 156 for the treatment of cancer wherein the cancer is Hodgkin'"'"'s Disease or anaplastic large cell lymphoma.

159. The method of claim 157 for the treatment of cancer wherein the cancer is Hodgkin'"'"'s Disease or anaplastic large cell lymphoma.

137. A composition comprising drug-linker-ligand conjugates having Formula Ia:

L

A_a-W_w-Y_y-D)_p 

 

Ia

or 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 -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 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 —

(CR^aR^b)_n—

where R^a and R^b 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).