Antibody Drug Conjugates Having Derivatives of Amatoxin As The Drug
There is disclosed derivatives of amanitin conjugated to a targeting antibody to form an ADC (antibody drug conjugate).
1 - 3 . (canceled)
4 . A compound having a structure of the following formula:
L 1 -L 2 -X-D
or a pharmaceutically acceptable salt thereof,
wherein:
L 1 -L 2 is a linker selected from
L 2 -X has a structure of
wherein R 4 is hydrogen or C 1-6 alkyl; and the wavy line indicates the point of attachment to D;
L 2 is a linker comprising (a) —R 6 OC(O)NR 5 —, and (b) —(CH 2 ) p —, —(CH 2 CH 2 O) m —, —C(O)NH—, —NHC(O)—, or a combination of two or more thereof, wherein:
R 5 is hydrogen, C 1-6 alkyl, —(CH 2 ) p —, —(CH 2 CH 2 O) m —, or a combination of two or more thereof;
R 6 is Val-Cit-PAB or Ala-Ala-Asn-PAB;
wherein —R 6 OC(O)NR 5 — is connected to L 1 through R 5 or R 6 ;
D is a drug moiety active agent derived from amatoxin having a structure of Formula (II):
wherein R 1 is NH 2 or OR 2 ; R 2 is H or C 1-10 alkyl; R 3 is H or OH; and the wavy line indicates the point of attachment to X;
m is an integer from 1-24; and
p is an integer from 1-6.
5 . The compound of claim 4 , wherein R 4 is C 1-6 alkyl.
6 . The compound of claim 5 , wherein R 4 is isopropyl.
7 . The compound of claim 5 , wherein R 4 is methyl.
8 . The compound of claim 5 , wherein L 1 -L 2 is
9 . The compound of claim 5 , wherein L 2 comprises (a) —R 6 OC(O)NR 5 — and (b) —(CH 2 ) p —.
10 . The compound of claim 4 , wherein R 6 is Ala-Ala-Asn-PAB.
11 . The compound of claim 4 , wherein R 6 is Val-Cit-PAB.
12 . The compound of claim 4 , wherein R 5 is —(CH 2 ) p —.
13 . The compound of claim 4 , wherein R 5 is C 1-6 alkyl.
14 . The compound of claim 13 , wherein R 5 is methyl.
15 . The compound of claim 4 , wherein D has a structure of Formula (II):
wherein R 1 is NH 2 or OH; R 3 is H or OH; and the wavy line indicates the point of attachment to X.
16 . The compound of claim 4 , which is selected from:
17 . The compound of claim 16 , having the structure:
18 . An antibody drug conjugate (ADC) having the structure of Formula (I):
Ab L 1 -L 2 -X-D) n (I)
or a pharmaceutically acceptable salt thereof,
wherein:
Ab is a monoclonal antibody;
L 1 -L 2 is a linker selected from
wherein the wavy line indicates the point of attachment to Ab;
L 2 -X has a structure of
wherein R 4 is hydrogen or C 1-6 alkyl; and the wavy line indicates the point of attachment to D;
L 2 is a linker comprising —R 8 —S—S—R 7 —, wherein:
R 7 is C 2-6 alkylene or —(CH 2 CH 2 O) m —;
R 8 is selected from C 1-6 alkyl, C 1-6 alkylene, substituted C 1-6 alkylene, —C(O)NH—, —C(O)—NH—CHR 9 —CR 10 R 11 —, —NHC(O)—CHR 9 —CR 10 R 11 —, —(CH 2 CH 2 O) m —, and combinations thereof;
R 9 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkylene, —(CH 2 CH 2 O) m —, —C(O)NH—, —NHC(O)—, —C(O)NH—(CH 2 ) p —SO 3 H, C(O)NH—(CH 2 ) p —CO 2 H, —NHC(O)—(CH 2 ) p —SO 3 H, —NHC(O)—(CH 2 ) p —CO 2 H, and combinations thereof;
R 10 and R 11 are each independently selected from hydrogen, C 1-6 alkyl, and combinations thereof;
wherein —R 8 —S—S—R 7 — is connected to L 1 through R 8 ;
D is a drug moiety active agent derived from amatoxin having a structure of Formula (II):
wherein R 1 is NH 2 or OR 2 ; R 2 is H or C 1-10 alkyl; R 3 is H or OH; and the wavy line indicates the point of attachment to X;
n is an integer from 1-10;
m is an integer from 1-24; and
p is an integer from 1-6.
19 . The ADC of claim 18 , wherein L 1 -L 2 is:
20 . The ADC of claim 18 , wherein R 4 is C 1-6 alkyl.
21 . The ADC of claim 20 , wherein R 4 is methyl.
22 . The ADC of claim 18 , wherein R 7 is C 2-6 alkylene.
23 . The ADC of claim 18 , where Ab is an anti-HER2 antibody.
24 . The ADC of claim 18 , wherein the ADC is:
25 . A compound having the structure of the following formula:
L 1 -L 2 -X-D
or a pharmaceutically acceptable salt thereof,
wherein:
L 1 -L 2 is a linker selected from
L 2 -X has a structure of
wherein R 4 is hydrogen or C 1-6 alkyl; and the wavy line indicates the point of attachment to D;
L 2 is a linker comprising —R 8 —S—S—R 7 —, wherein:
R 7 is C 2-6 alkylene or —(CH 2 CH 2 O) m —;
R 8 is selected from C 1-6 alkyl, C 1-6 alkylene, substituted C 1-6 alkylene, —C(O)NH—, —C(O)—NH—CHR 9 —CR 10 R 11 —, —NHC(O)—CHR 9 —CR 10 R 11 —, —(CH 2 CH 2 O) m —, and combinations thereof;
R 9 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkylene, —(CH 2 CH 2 O) m —, —C(O)NH—, —NHC(O)—, —C(O)NH—(CH 2 ) p —SO 3 H, C(O)NH—(CH 2 ) p —CO 2 H, —NHC(O)—(CH 2 ) p —SO 3 H, —NHC(O)—(CH 2 ) p —CO 2 H, and combinations thereof;
R 10 and R 11 are each independently selected from hydrogen, C 1-6 alkyl, and combinations thereof;
wherein —R 8 —S—S—R 7 — is connected to L 1 through R 8 ;
D is a drug moiety active agent derived from amatoxin having a structure of Formula (II):
wherein R 1 is NH 2 or OR 2 ; R 2 is H or C 1-10 alkyl; R 3 is H or OH; and the wavy line indicates the point of attachment to X;
m is an integer from 1-24; and
p is an integer from 1-6.
26 . The compound of claim 25 , wherein L 1 -L 2 is:
27 . The compound of claim 25 , wherein R 4 is C 1-6 alkyl.
28 . The compound of claim 27 , wherein R 4 is methyl.
29 . The compound of claim 25 , wherein R 7 is C 2-6 alkylene.
30 . The compound of claim 25 , wherein the compound is:
31 . A method of treating a cancer in an individual in need thereof, comprising administering an effective amount of the ADC of claim 18 to the individual.
32 . A method of treating a cancer in an individual in need thereof, comprising administering an effective amount of an antibody drug conjugate (ADC) to the individual, wherein the ADC has the structure of Formula (I):
Ab L 1 -L 2 -X-D) n (I)
or a pharmaceutically acceptable salt thereof,
wherein:
Ab is a monoclonal antibody;
L 1 -L 2 is a linker selected from
wherein the wavy line indicates the point of attachment to Ab;
L 2 -X has a structure of
wherein R 4 is hydrogen or C 1-6 alkyl, and the wavy line indicates the point of attachment to D;
L 2 is a linker comprising (a) —R 6 OC(O)NR 5 —, and (b) —(CH 2 ) p —, —(CH 2 CH 2 O) m —, —C(O)NH—, —NHC(O)—, or a combination of two or more thereof, wherein:
R 5 is hydrogen, C 1-6 alkyl, —(CH 2 ) p —, —(CH 2 CH 2 O) m —, or a combination of two or more thereof;
R 6 is Val-Cit-PAB or Ala-Ala-Asn-PAB;
wherein —R 6 OC(O)NR 5 — is connected to L 1 through R 5 or R 6 ;
D is a drug moiety active agent derived from amatoxin having a structure of Formula (II):
wherein R 1 is NH 2 or OR 2 , R 2 is H or C 1-10 alkyl, and R 3 is H or OH; and
the wavy line indicates the point of attachment to X;
n is an integer from 1-10;
m is an integer from 1-24; and
p is an integer from 1-6.