Multi-drug antibody drug conjugates
The present disclosure provides, inter alia, multi-drug Antibody Drug Conjugates (MD-ADCs) and Linking Assembly (LA) Units, that are constructed in a site-specific matter via ‘orthogonal’ deprotection and drug loading. Also provided are, Protected Linking Assembly Units, which allow for ‘orthogonal’ deprotection and construction of MD-ADCs and LA Units of the present disclosure.
1. A multi-drug antibody drug conjugate having the structure:
or in a hydrolyzed form wherein the succinimide is hydrolyzed, wherein
Ab* is an antibody comprising one or more engineered cysteine residues;
X is an Attachment Group Linker;
D 1 is a first Drug Unit;
D 2 is a second Drug Unit, wherein D 1 and D 2 are different Drug Units;
L 1 is an Optional Linking Group;
L 2 is an Optional Linking Group; and
P 1 is a polyethylene glycol group.
2. The antibody drug conjugate of claim 1 , wherein each of L 1 and L 2 is independently selected from the group consisting of maleimido-caproyl (mc), maleimido-caproyl-valine-citrulline (mc-vc), and maleimido-caproyl-valine-citrulline-paraaminobenzyloxycarbonyl (mc-vc-PABC), wherein the maleimido group is replaced by a succinimido group, optionally in a hydrolyzed form.
3. The antibody drug conjugate of claim 1 , wherein D 1 and D 2 are independently selected from: the group consisting of MMAE, Auristatin T, MMAF and Dolastatin 10; or the group consisting of MMAE, camptothecin, Superdox, Dolastatin 10, Vinblastine and Ciprofloxacin.
4. The antibody drug conjugate of claim 1 , wherein D 1 and D 2 are a drug pair selected from the group consisting of MMAE/MMAF, MMAE/camptothecin, Superdox/camptothecin, Superdox/MMAE, Dolastatin 10/MMAE, Dolastatin 10/MMAF, Vinblastine/MMAE, and Vinblastine/MMAF.
5. The antibody drug conjugate of claim 1 , wherein D 1 and D 2 are a first anticancer agent and a second anticancer agent, respectively.
6. The antibody drug conjugate of claim 5 , wherein the first anticancer agent and the second anticancer agent have complementary activity profiles.
7. The antibody drug conjugate of claim 5 , wherein the first anticancer agent and the second anticancer agent are MMAE and MMAF or camptothecin and doxorubicin.
8. The antibody drug conjugate of claim 1 , wherein the two Drug Units attached to the Linking Assembly Units are produced by thiol/maleimide coupling.
9. The antibody drug conjugate of claim 1 , wherein X is an amino acid or a di- or tri-peptide.
10. The antibody drug conjugate of claim 9 , wherein each amino acid present in X is selected from the group consisting of glycine and alanine.
11. A multi-drug antibody drug conjugate having the structure:
wherein
Ab is an antibody that is a non-engineered antibody;
D 1 is a first Drug Unit;
D 2 is a second Drug Unit, wherein D 1 and D 2 are different Drug Units;
L 1 is an Optional Linking Group;
L 2 is an Optional Linking Group; and
P 1 is a polyethylene glycol group.
12. The antibody drug conjugate of claim 11 , wherein each of L 1 and L 2 is independently selected from the group consisting of maleimido-caproyl (mc), maleimido-caproyl-valine-citrulline (mc-vc), and maleimido-caproyl-valine-citrulline-paraaminobenzyloxycarbonyl (mc-vc-PABC), wherein the maleimido group is replaced by a succinimido group, optionally in a hydrolyzed form.
13. The antibody drug conjugate of claim 11 , wherein D 1 and D 2 are independently selected from: the group consisting of MMAE, Auristatin T, MMAF and Dolastatin 10; or the group consisting of MMAE, camptothecin, Superdox, Dolastatin 10, Vinblastine and Ciprofloxacin.
14. The antibody drug conjugate of claim 11 , wherein D 1 and D 2 are a drug pair selected from the group consisting of MMAE/MMAF, MMAE/camptothecin, Superdox/camptothecin, Superdox/MMAE, Dolastatin 10/MMAE, Dolastatin 10/MMAF, Vinblastine/MMAE, and Vinblastine/MMAF.
15. A multi-drug antibody drug conjugate having a structure selected from the group consisting of:
wherein