Antibody drug conjugates
There is disclosed a Dolastatin derivative, conjugated to an antibody, comprising a Dolastatin derivative moiety of Formula IV.
1. A compound comprising Formula IV:
wherein Y is OH or NH 2 ; and
X is —CH 2 N 3 .
2. An antibody drug-conjugate (ADC) comprising Formula I:
Ab L 1 -L 2 -D) n (I)
or a pharmaceutically acceptable salt thereof,
wherein:
Ab is a monoclonal antibody;
L 1 is a connector;
L 2 is a linker comprising an amino acid, peptide, (CH 2 ) n —, —(CH 2 CH 2 O) n —, —(C═O)—, -Val-Cit-, -Val-Ala-, -Ala-Ala-Asn-, -Ala-Val-Asn-, —(C═O)CH 2 CH 2 (C═O)—, —(C═O)CH 2 CH 2 O)—, —(CH 2 CH 2 O) n —CH 2 CH 2 NH—, —(C═O)—CH 2 —, or
a combination thereof;
D is an active agent (Drug) having a structure of Formula II
wherein Y is O or NH,
X is CH 2 N 3 ; and
n is an integer from 1-8.
3. The ADC of claim 2 , wherein the structure of Formula I has a structure selected from the group consisting of
4. The ADC of claim 2 , wherein L 2 is selected from the group consisting of —(C═O)—, —CH 2 (C═O)—, -Cit-Val-(C═O)CH 2 CH 2 (C═O)—, -Asn-Ala-Ala-(C═O) CH 2 CH 2 (C═O)—, -Asn-Val-Ala-(C═O) CH 2 CH 2 (C═O)—, -Cit-Val-(C═O) CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 —, -Cit-Val-(C═O) CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 NH—, -Asn-Ala-Ala-(C═O)CH 2 CH 2 O(CH 2 CH 2 O) n CH 2 CH 2 NH(C═O)—,
5. The compound of claim 1 , wherein Y is OH.
6. The compound of claim 1 , wherein Y is NH 2 .
7. The ADC of claim 2 , wherein L 1 comprises
8. The ADC of claim 2 , wherein Y is NH.
9. The ADC of claim 2 , wherein Y is O.
10. The ADC of claim 2 , wherein -L 1 -L 2 , taken together with Ab, is selected from the group consisting of
11. The ADC of claim 2 , wherein L 1 comprises
12. The ADC of claim 2 , wherein L 1 comprises
13. The ADC of claim 2 , wherein -L 1 -L 2 , taken together with Ab, is
14. The ADC of claim 2 , wherein -L 1 -L 2 , taken together with Ab, is