Antibody-polymer-drug conjugates

Patent metadata

Field	Value
Publication number	US-11801307-B2
Application number	US-201716334301-A
Country	US
Kind code	B2
Filing date	Oct 13, 2017
Priority date	Oct 14, 2016
Publication date	Oct 31, 2023
Grant date	Oct 31, 2023

Abstract

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.

First claim

What is claimed is:

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).

Assignees

• Univ Utah Res Found

Inventors

• Yang Jiyuan
• Kopecek Jindrich
• Zhang Libin
• Fang Yixin

Classifications

• A61K47/6883 Primary

  Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy · CPC title

• A61K38/07

  Tetrapeptides · CPC title

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• A61K47/58

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin · CPC title

• A61P35/00

  Antineoplastic agents · CPC title