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 which is a chemotherapy drug, tubulin-binder, DNA alkylating agent, HSP90 inhibitor, a DNA topoisomerase inhibitor, an HDAC inhibitor, a proteasome inhibitor, epothilone A, epothilone B, a cytotoxic peptide or paclitaxel;
each L 2 is independently a linker, 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:
is:
5. The active agent-conjugate of claim 1 , wherein the A component comprises at least one modified L-Alanine residue.
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 B is null.
8. 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.
9. 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.
10. The active agent-conjugate of claim 1 , wherein L 2 comprises a peptide, an oligosaccharide, or a combination thereof.
11. The active agent-conjugate of claim 1 , wherein L 2 comprises 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.
12. The active agent-conjugate of claim 1 , wherein L 2 comprises a noncleavable unit.
13. The active agent-conjugate of claim 1 , wherein L 2 comprises a cleavable unit.
14. A method of treating a patient having cancer, comprising administering an active agent-conjugate according to claim 1 to the patient.