IMMUNOCONJUGATES AND METHODS
Immunoconjugates of the Formula (I) include a linking group for linking an antibody targeting ligand (Ab) to a drug (D). Embodiments of such immunoconjugates are useful for delivering the drug to selected cells or tissues, e.g., for the treatment of cancer. Formula (I)
1 . An immunoconjugate having Formula (I),
wherein:
Ab is an antibody or an antigen-binding fragment thereof;
L 1 is
L 2 is absent,
Z 1 and Z 2 are each individually hydrogen, halogen, NO 2 , —O—(C 1 -C 6 alkyl), or C 1 -C 6 alkyl;
L 3 is —(CH 2 )n 1 -C(═O)— or —(CH 2 CH 2 O)n 1 -(CH 2 )n 1 C(═O)—;
n 1 are independently integers of 0 to 12;
L 4 is a tetrapeptide residue;
L 5 is absent or —[NH(CH 2 )n 2 ]n 3 -;
n 2 is an integer of 0 to 6;
n 3 is an integer of 0 to 2;
L 6 is absent or
L 7 is absent,
D is a drug moiety; and
n is an integer from 1 to 10;
wherein D is a drug moiety of Formula (II) having the structure:
wherein:
R 1 and R 2 are each individually selected from the group consisting of hydrogen, halogen, —CN, —OR 5 , —NR 5 R 6 , a substituted or an unsubstituted C 1 -C 6 alkyl, a substituted or an unsubstituted C 1 -C 6 haloalkyl, a substituted or an unsubstituted —O—(C 1 -C 6 alkyl), a substituted or an unsubstituted —O—(C 1 -C 6 haloalkyl), and —[(CY 2 ) p O(CY 2 ) q ] t CY 3 , or a substituted or an unsubstituted —O—(CR 5 R 6 ) m —O— such that R 1 and R 2 taken together form a ring;
R 3 is selected from the group consisting of hydrogen, —OR 5 , —NR 5 R 6 , a substituted or an unsubstituted C 1 -C 6 alkyl, a substituted or an unsubstituted C 2 -C 6 alkenyl, a substituted or an unsubstituted C 2 -C 6 alkynyl, a substituted or unsubstituted 4- or 5-membered heterocyclyl, and [(CY 2 ) p O(CY 2 ) q ] t CY 3 ;
R 4 is selected from the group consisting of substituted or unsubstituted —(C 1 -C 6 alkyl)-X 2 , substituted or unsubstituted —(C 1 -C 6 haloalkyl)-X 2 , substituted or unsubstituted —(C 1 -C 6 alkenyl)-X 2 , substituted or unsubstituted —(C 1 -C 6 haloalkenyl)-X 2 , substituted or unsubstituted —(C 1 -C 6 alkynyl)-X 2 , and substituted or unsubstituted —(C 1 -C 6 haloalkynyl)-X 2
X 2 is —OR 9 , —SR 9 , or —NHR 9 ;
R 5 and R 6 are each individually a substituted or an unsubstituted C 1 -C 6 alkyl; or R 5 and R 6 , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 4- or 5-membered heterocyclyl;
n 4 and n 5 are each individually 0, 1 or 2, with the proviso that n 4 and n 5 are not both 0;
each Y is individually H or halogen;
each m is individually 1 or 2;
each p is individually 1, 2, 3, 4, 5, or 6;
each t is individually 0, 1, 2, 3, 4, 5, or 6;
each t is individually 1, 2, 3, 4, 5, or 6;
R 7 is H, —COR 8 , —CO 2 R 8 , —(CO)—NHR 8 , L 4 , L 5 , L 6 , or L 7 ;
R 8 is a substituted or an unsubstituted C 1 -C 6 alkyl-X 3 , a substituted or an unsubstituted C 1 -C 6 haloalkyl-X 3 , or —[(CY 2 ) p O(CY 2 ) q ] t CY 2 —X 3 ;
R 9 is H, —COR 8 , —CO 2 R 8 , —(CO)—NHR 8 , L 4 , L 5 , L 6 , or L 7 , with the proviso that exactly one of R 7 and R 9 is L 4 , L 5 , L 6 , or L 7 ; and
each X 3 is individually —H, —OH, —SH, or —NH 2 .
2 - 11 . (canceled)
12 . The immunoconjugate of claim 1 , wherein L 4 is gly-gly-phe-gly (GGFG).
13 - 21 . (canceled)
22 . The immunoconjugate of claim 21 , wherein R 1 is C 1 -C 3 alkyl and R 2 is a halogen.
23 . The immunoconjugate of claim 21 , wherein R 1 is methyl and R 2 is F.
24 - 56 . (canceled)
57 . The immunoconjugate of claim 1 , wherein the immunoconjugate of Formula (I) is selected from the group consisting of:
58 . The immunoconjugate of claim 1 , wherein the immunoconjugate of Formula (I) is selected from the group consisting of:
59 . The immunoconjugate of claim 1 , wherein the immunoconjugate of Formula (I) is selected from the group consisting of:
60 . The immunoconjugate of claim 1 , wherein the immunoconjugate of Formula (I) is selected from the group consisting of:
61 . The immunoconjugate of claim 1 , wherein the immunoconjugate of Formula (I) is selected from the group consisting of:
62 . A compound of Formula (IV), or a pharmaceutically acceptable salt thereof, having the structure:
wherein:
R 1 and R 2 are each individually selected from the group consisting of hydrogen, halogen, —CN, —OR 5 , —NR 5 R 6 , a substituted or an unsubstituted C 1 -C 6 alkyl, a substituted or an unsubstituted C 1 -C 6 haloalkyl, a substituted or an unsubstituted —O—(C 1 -C 6 alkyl), a substituted or an unsubstituted —O—(C 1 -C 6 haloalkyl), and —[(CY 2 ) p O(CY 2 ) q ] t CY 3 , or a substituted or an unsubstituted —O—(CR 5 R 6 ) m —O— such that R 1 and R 2 taken together form a ring;
R 3 is selected from the group consisting of hydrogen, —OR 5 , —NR 5 R 6 , a substituted or an unsubstituted C 1 -C 6 alkyl, a substituted or an unsubstituted C 2 -C 6 alkenyl, a substituted or an unsubstituted C 2 -C 6 alkynyl, a substituted or unsubstituted 4- or 5-membered heterocyclyl, and —[(CY 2 ) p O(CY 2 ) q ] t CY 3 ;
R 4 is selected from the group consisting of a substituted or an unsubstituted C 1 -C 6 alkyl, a substituted or an unsubstituted C 2 -C 6 alkenyl, a substituted or an unsubstituted C 2 -C 6 alkynyl;
R 5 and R 6 are each individually a substituted or an unsubstituted C 1 -C 6 alkyl; or R 5 and R 6 , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 4- or 5-membered heterocyclyl;
n 4 and n 5 are each individually 0, 1 or 2, with the proviso that n 4 and n 5 are not both 0;
each Y is individually H or halogen;
each m is individually 1 or 2;
each p is individually 1, 2, 3, 4, 5, or 6;
each q is individually 0, 1, 2, 3, 4, 5, or 6; and
each t is individually 1, 2, 3, 4, 5, or 6;
R 7 is H, —COR 8 , —CO 2 R 8 , or —(CO)—NHR 8 ; and
R 8 is a substituted or an unsubstituted C 1 -C 6 alkyl, a substituted or an unsubstituted C 1 -C 6 haloalkyl, or —[(CY 2 ) p O(CY 2 ) q ] t CY 3 .
63 . The compound of claim 62 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 3 alkyl and R 2 is a halogen.
64 . The compound of claim 62 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl and R 2 is F.
65 - 95 . (canceled)
96 . The compound of claim 62 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (IV) is selected from the group consisting of:
97 . The compound of claim 62 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (IV) is selected from the group consisting of:
98 . The compound of claim 62 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (IV) is selected from the group consisting of:
99 . The compound of claim 62 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (IV) is selected from the group consisting of:
100 . A pharmaceutical composition comprising an immunoconjugate of claim 1 , or a pharmaceutically active salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
101 . A method for treating a cancer or a tumor comprising administering an effective amount of claim 1 , or a pharmaceutically active salt thereof, to a subject having the cancer or the tumor.
102 . The method of claim 101 , wherein the cancer or the tumor is selected from lung cancer, urothelial cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, breast cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, uterine cervix cancer, esophageal cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, or sarcoma.
103 - 104 . (canceled)
105 . A conjugate having Formula (III),
wherein:
Mi is
L 2 is absent,
Z 1 and Z 2 are each individually hydrogen, halogen, NO 2 , —O—(C 1 -C 6 alkyl), or C 1 -C 6 alkyl;
L 3 is —(CH 2 )n 1 -C(═O)— or —(CH 2 CH 2 O)n 1 -(CH 2 )n 1 C(═O)—;
n 1 are independently integers of 0 to 12;
L 4 is a tetrapeptide residue;
L 5 is absent or —[NH(CH 2 )n 2 ]n 3 -;
n 2 is an integer of 0 to 6;
n 3 is an integer of 0 to 2;
L 6 is absent or
L 7 is absent,
and
D is a drug moiety of Formula (II) having the structure:
wherein:
R 1 and R 2 are each individually selected from the group consisting of hydrogen, halogen, —CN, —OR 5 , —NR 5 R 6 , a substituted or an unsubstituted C 1 -C 6 alkyl, a substituted or an unsubstituted C 1 -C 6 haloalkyl, a substituted or an unsubstituted —O—(C 1 -C 6 alkyl), a substituted or an unsubstituted —O—(C 1 -C 6 haloalkyl), and —[(CY 2 ) p O(CY 2 ) q ] t CY 3 , or a substituted or an unsubstituted —O—(CR 5 R 6 ) m —O— such that R 1 and R 2 taken together form a ring;
R 3 is selected from the group consisting of hydrogen, —OR 5 , —NR 5 R 6 , a substituted or an unsubstituted C 1 -C 6 alkyl, a substituted or an unsubstituted C 2 -C 6 alkenyl, a substituted or an unsubstituted C 2 -C 6 alkynyl, a substituted or unsubstituted 4- or 5-membered heterocyclyl, and [(CY 2 ) p O(CY 2 ) q ] t CY 3 ;
R 4 is selected from the group consisting of substituted or unsubstituted —(C 1 -C 6 alkyl)-X 2 , substituted or unsubstituted —(C 1 -C 6 haloalkyl)-X 2 , substituted or unsubstituted —(C 1 -C 6 alkenyl)-X 2 , substituted or unsubstituted —(C 1 -C 6 haloalkenyl)-X 2 , substituted or unsubstituted —(C 1 -C 6 alkynyl)-X 2 , and substituted or unsubstituted —(C 1 -C 6 haloalkynyl)-X 2
X 2 is —OR 9 , —SR 9 , or —NHR 9 ;
R 5 and R 6 are each individually a substituted or an unsubstituted C 1 -C 6 alkyl; or R 5 and R 6 , taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 4- or 5-membered heterocyclyl;
n 4 and n 5 are each individually 0, 1 or 2, with the proviso that n 4 and n 5 are not both 0;
each Y is individually H or halogen;
each m is individually 1 or 2;
each p is individually 1, 2, 3, 4, 5, or 6;
each t is individually 0, 1, 2, 3, 4, 5, or 6;
each t is individually 1, 2, 3, 4, 5, or 6;
R 7 is H, —COR 8 , —CO 2 R 8 , —(CO)—NHR 8 , L 4 , L 5 , L 6 , or L 7 ;
R 8 is a substituted or an unsubstituted C 1 -C 6 alkyl-X 3 , a substituted or an unsubstituted C 1 -C 6 haloalkyl-X 3 , or —[(CY 2 ) p O(CY 2 ) q ] t CY 2 —X 3 ;
R 9 is H, —COR 8 , —CO 2 R 8 , —(CO)—NHR 8 , L 4 , L 5 , L 6 , or L 7 , with the proviso that exactly one of R 7 and R 9 is L 4 , L 5 , L 6 , or L 7 ; and
each X 3 is individually —H, —OH, —SH, or —NH 2 .
106 - 115 . (canceled)
116 . The conjugate of claim 105 , wherein L 4 is gly-gly-phe-gly (GGFG).
117 - 125 . (canceled)
126 . The conjugate of claim 125 , wherein R 1 is C 1 -C 3 alkyl and R 2 is a halogen.
127 . The conjugate of claim 125 or 126 , wherein R 1 is methyl and R 2 is F.
128 - 158 . (canceled)
159 . The conjugate of claim 105 , wherein the conjugate having Formula (III) is selected from the group consisting of:
160 . The conjugate of claim 105 , wherein the conjugate having Formula (III) is selected from the group consisting of:
161 . The conjugate of claim 105 , wherein the conjugate having Formula (III) is selected from the group consisting of:
162 . The conjugate of claim 105 , wherein the conjugate having Formula (III) is selected from the group consisting of:
163 . The conjugate of claim 105 , wherein the conjugate having Formula (III) is selected from the group consisting of:
164 - 175 . (canceled)