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. An antibody drug conjugate (ADC) having the structure of Formula (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.
2. The ADC of claim 1 , wherein the ADC is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
3. The ADC of claim 1 , wherein R 4 is C 1-6 alkyl.
4. The ADC of claim 3 , wherein L 1 -L 2 is
wherein the bond of L 2 to X is not shown, and the wavy line indicates the point of attachment of L 1 to Ab.
5. The ADC of claim 3 , wherein L 2 comprises (a) —R 6 OC(O)NR 5 — and (b) —(CH 2 ) p —.
6. The ADC of claim 1 , wherein n is 1.
7. The ADC of claim 1 , wherein R 6 is Ala-Ala-Asn-PAB.
8. The ADC of claim 1 , wherein R 5 is —(CH 2 ) p —.
9. The ADC of claim 1 , wherein D has a structure of Formula (II):
wherein R 1 is NH 2 or OH, and R 3 is H or OH;
and the wavy line indicates the point of attachment to X.
10. The ADC of claim 1 , wherein R 6 is -Val-Cit-PAB-.
11. The ADC of claim 1 , wherein R 4 is isopropyl.
12. The ADC of claim 1 , having the structure of Formula (29)
or a pharmaceutically acceptable salt thereof.
13. The ADC of claim 1 , wherein R 5 is C 1-6 alkyl.
14. The ADC of claim 13 , wherein R 5 is methyl.
15. The ADC of claim 3 , wherein R 4 is methyl.
16. The ADC of claim 1 , having the structure
17. The ADC of claim 1 , where Ab is an anti-HER2 antibody.