Antibody-polymer-drug conjugates
Disclosed herein, are antibody-polymer-drug conjugates. The conjugate comprises a targeting moiety, one or more polymers, and one or more therapeutic agents. Also described herein, are compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders with the conjugates or their compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
1. An antibody-polymer-drug conjugate comprising:
a targeting antibody bonded to a polymer comprising:
a first monomer residue having a structure:
wherein R 1 is hydrogen or methyl, wherein X is oxygen or NR 1 ′, wherein R 1 ′ is hydrogen or an alkyl group, wherein L is an alkyl group or an aryl group, and wherein Y is a hydrophilic group;
and
a second monomer residue having a structure
wherein R 2 is hydrogen or methyl, wherein Z is a therapeutic agent,
wherein TALG is an oligopeptide therapeutic agent linking group which is stable under physiologic conditions and cleaved in lysosomal compartment and
wherein the targeting antibody is bonded to the polymer via a linkage having the structure:
2. The conjugate of claim 1 , wherein targeting antibody is abciximab, adalimumab, alemtuzumab, basiliximab, belimumab, bevacizumab, brentuximab, canakinumab, cetuximab, daclizumab, efalizumab, gemtuzumab, golimumab, ibritumomab, infliximab, ipilimumab, motavizumab, obinutuzumab, ofatumumab, omalizumab, OV-TL-16, palivizumab, pertuzumab, ranibizumab, raxibacumab, rituximab, tocilizumab, trastuzumab, or ustekinumab.
3. The conjugate of claim 1 , wherein the targeting antibody is an anti-CD20 monoclonal antibody, an anti-OA-3 monoclonal antibody, or an anti-HER2 monoclonal antibody.
4. The conjugate of claim 1 , wherein the therapeutic agent linking group is Gly-Gly, Gly-Phe-Gly, Gly-Phe-Phe, Gly-Leu-Gly, Gly-Val-Ala, Gly-Val-Leu, Gly-Val-Phe, Gly-Phe-Ala, Gly-Leu-Phe, Gly-Leu-Ala, Gly-Ile-Ala, Ala-Val-Ala, Ala-Val-Phe, Ala-Phe-Val, Gly-Phe-Leu-Gly (SEQ ID NO: 1), Gly-Phe-Phe-Leu (SEQ ID NO: 2), Gly-Leu-Leu-Gly (SEQ ID NO: 3), Gly-Phe-Tyr-Ala (SEQ ID NO: 4), Gly-Phe-Gly-Phe (SEQ ID NO: 5), Ala-Gly-Val-Phe (SEQ ID NO: 6), Gly-Phe-Phe-Gly (SEQ ID NO: 7), Gly-Phe-Leu-Gly-Phe (SEQ ID NO: 8), Gly-Gly-Phe-Leu-Gly-Phe (SEQ ID NO: 9), N-aminocaproyl-Val-Citruline, or a combination thereof.
5. The conjugate of claim 1 , wherein the therapeutic agent is an anti-cancer agent.
6. The conjugate of claim 1 , further comprising residues of a monomer selected from the group consisting of N-(2-hydroxypropyl) methacrylamide, 2-hydroxyethyl methacrylate, diethylene glycol monomethacrylate, triethylene glycol monomethacrylate, acrylonitrile, methacrylonitrile, acrylamide, methacrylamide, N-alkylmethacrylamide, N-alkylacrylamide, N,N-dialkylacrylamide, methacrylic acid, acrylic acid, esters of acrylic acid, esters of methacrylic acid, N,N-diethylaminoethyl methacrylate, N-vinylpyrrolidone, norbornene, and combinations thereof.
7. A pharmaceutical composition comprising the conjugate of claim 1 and a pharmaceutically acceptable carrier.
8. The conjugate of claim 1 , wherein the targeting antibody is rituximab, Herceptin or OV-TL16, the first monomer residue is a residue of N-(2-hydroxypropyl) methacrylamide, and the therapeutic agent is epirubicin.
9. The conjugate of claim 1 , wherein the therapeutic agent is selected from epirubicin, doxorubicin, daunorubicin, idarubicin, paclitaxel, 10-deacetylbaccatin III, baccatin III, paclitaxel C, and 7-epipaclitaxel.
10. The conjugate of claim 1 , wherein the first monomer residue is a residue of HEMA or HPMA.
11. The antibody-polymer-drug conjugate of claim 1 ,
wherein the first monomer residue is a residue of HEMA or HPMA;
wherein the therapeutic agent linking group is Gly-Gly, Gly-Phe-Gly, Gly-Phe-Phe, Gly-Leu-Gly, Gly-Val-Ala, Gly-Val-Leu, Gly-Val-Phe, Gly-Phe-Ala, Gly-Leu-Phe, Gly-Leu-Ala, Gly-Ile-Ala, Ala-Val-Ala, Ala-Val-Phe, Ala-Phe-Val, Gly-Phe-Leu-Gly (SEQ ID NO: 1), Gly-Phe-Phe-Leu (SEQ ID NO: 2), Gly-Leu-Leu-Gly (SEQ ID NO: 3), Gly-Phe-Tyr-Ala (SEQ ID NO: 4), Gly-Phe-Gly-Phe (SEQ ID NO: 5), Ala-Gly-Val-Phe (SEQ ID NO: 6), Gly-Phe-Phe-Gly (SEQ ID NO: 7), Gly-Phe-Leu-Gly-Phe (SEQ ID NO: 8), Gly-Gly-Phe-Leu-Gly-Phe (SEQ ID NO: 9), N-aminocaproyl-Val-Citruline, or a combination thereof;
wherein the therapeutic agent is selected from epirubicin, doxorubicin, daunorubicin, idarubicin, paclitaxel, 10-deacetylbaccatin III, baccatin III, paclitaxel C, and 7-epipaclitaxel;
wherein Ab is the targeting antibody; and
wherein the targeting antibody is abciximab, adalimumab, alemtuzumab, basiliximab, belimumab, bevacizumab, brentuximab, canakinumab, cetuximab, daclizumab, efalizumab, gemtuzumab, golimumab, ibritumomab, infliximab, ipilimumab, motavizumab, obinutuzumab, ofatumumab, omalizumab, OV-TL-16, palivizumab, pertuzumab, ranibizumab, raxibacumab, rituximab, tocilizumab, trastuzumab, or ustekinumab.
12. The conjugate of claim 1 , wherein the second monomer residue has a structure:
wherein the oligopeptide therapeutic agent linking group is Gly-Phe-Leu-Gly (SEQ ID NO: 1).