Drug-conjugates, conjugation methods, and uses thereof
In one aspect, an active agent-conjugate, methods of preparing the active agent-conjugate, and uses thereof is provided.
1. An active agent-conjugate comprising Formula Ia:
or a pharmaceutically acceptable salt thereof,
wherein:
the A-component is an antibody or an antibody fragment;
the E-component is selected from the group consisting of:
L 3 is an optionally substituted C 1 -C 6 alkyl, or L 3 is null, wherein when L 3 is null the sulfur is directly connected to the E-component;
L 4 is an optionally substituted C 1 -C 6 alkyl, or L 4 is null, wherein when L 4 is null the sulfur is directly connected to the E-component;
B is a hydrophilic polymer, a biodegradable polymer, a polyamino acid, a polypeptide, a polysaccharide, a monoclonal antibody, an antibody fragment, a protein ligand, a protein scaffold, a peptide, or a nucleic acid, or B is null;
each D is independently selected, wherein each D includes an active agent;
each L 2 independently comprises a —(CH 2 ) n —, —(CH 2 CH 2 O) n —, a peptide, an oligosaccharide, or a combination thereof; wherein L 2 links to E; and
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
2. The active agent-conjugate of claim 1 , wherein L 3 is —(CH 2 )— and L 4 is —(CH 2 )—.
3. The active agent-conjugate of claim 1 , wherein L 3 is null and L 4 is null.
4. The active agent-conjugate of claim 1 , wherein:
5. The active agent-conjugate of claim 1 , wherein said active agent is a chemotherapy drug, a tubulin-binder, a DNA-alkylating agent, an HSP90 inhibitor, a DNA topoisomerase inhibitor, an HDAC inhibitor, a proteasome inhibitor, a peptide, an siRNA, an antisense DNA, epothilone A, epothilone B, or paclitaxel.
6. The active agent-conjugate of claim 1 , wherein the A component comprises a monoclonal antibody.
7. The active agent-conjugate of claim 1 , wherein the A component comprises an antibody fragment.
8. The active agent-conjugate of claim 1 , wherein the A component comprises a protein ligand.
9. The active agent-conjugate of claim 1 , wherein the A component comprises a protein scaffold.
10. The active agent-conjugate of claim 1 , wherein the A component comprises a peptide.
11. The active agent-conjugate of claim 1 , wherein the A component comprises a small molecule ligand.
12. The active agent-conjugate of claim 1 , wherein the A component comprises at least one modified L-Alanine residue.
13. The active agent-conjugate of claim 1 , wherein the A component comprises at least two modified L-Alanine residues.
14. The active agent-conjugate of claim 1 , wherein B is null.
15. The active agent-conjugate of claim 1 , wherein L 2 comprises —(CH 2 ) n —, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
16. The active agent-conjugate of claim 1 , wherein L 2 comprises —(CH 2 CH 2 O) n —, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
17. The active agent-conjugate of claim 1 , wherein L 2 comprises a peptide, an oligosaccharide, or a combination thereof.
18. The active agent-conjugate of claim 1 , wherein L 2 comprises (CH 2 ) n —, —(CH 2 CH 2 O) n —, PAB, D-Val-Leu-Lys, Gly-Gly-Arg, Val-Cit-PAB, Val-Ala-PAB, Val-Lys (Ac)-PAB, Phe-Lys-PAB, Phe-Lys (Ac)-PAB, Ala-Ala-Asn-PAB, Ala-PAB, or a combination thereof.
19. The active agent-conjugate of claim 1 , wherein L 2 comprises a noncleavable unit.
20. The active agent-conjugate of claim 19 , wherein the noncleavable unit comprises —(CH 2 ) n —, and wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
21. The active agent-conjugate of claim 19 , wherein the noncleavable unit comprises —(CH 2 CH 2 O) n —, and wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
22. The active agent-conjugate of claim 1 , wherein L 2 comprises a cleavable unit.
23. The active agent-conjugate of claim 22 , wherein the cleavable unit comprises a peptide.