Claims for Patent: 10,364,451

Summary for Patent: 10,364,451

Title:	Polymer conjugates having reduced antigenicity and methods of using the same
Abstract:	Disclosed herein are compositions and methods for reducing the antigenicity of molecules. The antigenicity of a molecule may be reduced or eliminated by conjugating at least one branched polymer to the molecule to form a molecule-polymer conjugate. The branched polymer may include a backbone and a plurality of side chains, each side chain covalently attached to the backbone.
Inventor(s):	Chilkoti; Ashutosh (Durham, NC), Qi; Yizhi (Durham, NC), Hershfield; Michael S. (Durham, NC), Ganson; Nancy J. (Durham, NC)
Assignee:	Duke University (Durham, NC)
Application Number:	15/387,536
Patent Claims:	1. A method of reducing the antigenicity of a molecule, the method comprising conjugating at least one branched polymer to a molecule to form a molecule-polymer conjugate, wherein the molecule comprises a polypeptide, a polynucleotide, a small molecule, or a combination thereof, wherein the branched polymer comprises poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA), wherein the POEGMA comprises: a backbone comprising poly(methyl methacrylate); and a plurality of side chains covalently attached to the backbone, where each side chain comprises 2 to 9 monomers of ethylene glycol (EG) repeated in tandem; wherein the molecule-polymer conjugate is not reactive with pre-existing anti-PEG antibodies in a subject, and wherein the molecule-polymer conjugate has reduced or eliminated antigenicity compared to a control. 2. The method of claim 1, wherein the molecule is conjugated to the backbone of the branched polymer. 3. The method of claim 1, wherein each side chain has a first terminal end and a second terminal end, wherein the first terminal end is covalently attached to the backbone, and wherein the second terminal end independently comprises an alkyl, ester, amine, amide, or carboxyl group. 4. The method of claim 1, wherein each side chain has a first terminal end and a second terminal end, wherein the first terminal end is covalently attached to the backbone, and wherein the second terminal end does not include a hydroxyl group. 5. The method of claim 1, wherein each side chain comprises at least one monomer. 6. The method of claim 1, wherein the monomer of each side chain is independently selected from betaine, phosphorylcholine, phosphorylethanolamine, sarcosine, ethylene glycol, or a combination thereof. 7. The method of claim 1, wherein the molecule comprises a polypeptide, and wherein one branched polymer is conjugated to the polypeptide at a site selected from the C-terminus, the N-terminus, and an internal amino acid of the polypeptide. 8. The method of claim 1, wherein the molecule comprises a polypeptide comprising a sortase A recognition site, and wherein the branched polymer and the polypeptide are incubated with sortase A under conditions to conjugate the branched polymer to the sortase recognition site of the polypeptide. 9. The method of claim 1, wherein the branched polymer is synthesized and subsequently grafted to the molecule to form the molecule-polymer conjugate. 10. The method of claim 1, wherein the conjugating comprises attaching an initiator agent to the molecule to form a macroinitiator; and incubating the macroinitiator with a monomer under conditions that permit free-radical polymerization and formation of a branched polymer to occur from the initiator agent to form the molecule-polymer conjugate. 11. A method of making a molecule-polymer conjugate having reduced or eliminated antigenicity compared to a control, from a molecule comprising a polypeptide having a sortase A recognition site, the method comprising: a) contacting the molecule with a sortase A and an initiator agent under conditions that permit attachment of the initiator agent to the sortase A recognition site to form a macroinitiator; and b) incubating the macroinitiator with a monomer under conditions that permit free-radical polymerization and formation of a branched polymer to occur from the initiator agent to form the molecule-polymer conjugate, wherein the branched polymer comprises poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA), wherein the POEGMA comprises: a backbone comprising poly(methyl methacrylate); and a plurality of side chains covalently attached to the backbone, where each side chain comprises 2 to 9 monomers of ethylene glycol (EG) repeated in tandem; wherein the molecule-polymer conjugate is not reactive with pre-existing anti-PEG antibodies in a subject. 12. The method of claim 11, wherein the free-radical polymerization comprises at least one of atom transfer radical polymerization (ATRP), reversible addition-fragmentation chain transfer (RAFT), radical ring-opening polymerization (radical ROP), nitroxide-mediated radical polymerization (NMP), iniferter polymerization, free radical polymerization, cobalt-mediated radical polymerization, telluride-mediated polymerization, and stibine-mediated polymerization. 13. A molecule-polymer conjugate having reduced or eliminated antigenicity compared to a control, the molecule-polymer conjugate comprising: a branched polymer comprising poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA); and a molecule conjugated to the backbone of the branched polymer, wherein the molecule comprises a polypeptide, a polynucleotide, a small molecule, or a combination thereof, wherein the POEGMA comprises: a backbone comprising poly(methyl methacrylate); and a plurality of side chains covalently attached to the backbone, where each side chain comprises 2 to 9 monomers of ethylene glycol (EG) repeated in tandem; and wherein the molecule-polymer conjugate is not reactive with pre-existing anti-PEG antibodies in a subject. 14. The conjugate of claim 13, wherein each side chain has a first terminal end and a second terminal end, wherein the first terminal end is covalently attached to the backbone, and wherein the second terminal end independently comprises an alkyl, ester, amine, amide, or carboxyl group. 15. The conjugate of claim 13, wherein each side chain has a first terminal end and a second terminal end, wherein the first terminal end is covalently attached to the backbone, and wherein the second terminal end does not include a hydroxyl group. 16. The conjugate of claim 13, wherein each side chain comprises at least 3 monomers of ethylene glycol (EG) repeated in tandem. 17. The conjugate of claim 13, wherein the molecule comprises one or more peptides or protein therapeutic agents selected from a monoclonal antibody, blood factor, betatrophin, exendin, enzyme, asparaginase, glutamase, arginase, arginine deaminase, adenosine deaminase (ADA), ADA-2, ribonuclease, cytosine deaminase, trypsin, chymotrypsin, papain, growth factor, epidermal growth factor (EGF), insulin, insulin-like growth factor (IGF), transforming growth factor (TGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF), bone morphogenic protein (BMP), fibroblast growth factor (FGF), somatostatin, somatotropin, somatropin, somatrem, calcitonin, parathyroid hormone, colony stimulating factors (CSF), clotting factors, tumor necrosis factors (TNF), gastrointestinal peptides, vasoactive intestinal peptide (VIP), cholecystokinin (CCK), gastrin, secretin, erythropoietins, growth hormone , GRF, vasopressins, octreotide, pancreatic enzymes, superoxide dismutase, thyrotropin releasing hormone (TRH), thyroid stimulating hormone, luteinizing hormone, luteinizing hormone-releasing hormone (LHRH), growth hormone releasing hormone (GHRH), tissue plasminogen activators, interleukins, interleukin-1, interleukin-15, interleukin-2, interleukin-10, colony stimulating factor, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin-1 receptor antagonist (IL-1RA), glucagon-like peptide-1 (GLP-1), exenatide, GLP-1R multi-agonist, GLP-1 R antagonist, GLP-2, TNF-related apoptosis-inducing ligand (TRAIL), leptin, ghrelin, granulocyte monocyte colony stimulating factor (GM-CSF), interferons, interferon-.alpha., interferon-gamma, human growth hormone (hGH) and antagonist, macrophage activator, chorionic gonadotropin, heparin, atrial natriuretic peptide, hemoglobin, relaxin, cyclosporine, oxytocin, vaccines, monoclonal antibodies, single chain antibodies, ankyrin repeat proteins, affibodies, activin receptor 2A extracellular domain, alpha-2 macroglobulin, alpha-melanocyte, apelin, bradykinin B2 receptor antagonist, cytotoxic T-lymphocyte-associated protein (CTLA-4), elafin, Factor IX, Factor VIIa, Factor VIII, hepcidin, infestin-4, kallikrein inhibitor, L4F peptide, lacritin, parathyroid hormone (PTH), peptide YY (PYY), thioredoxin, thymosin B4, urate oxidase, urodilatin, aptamers, silencing RNA, microRNA, long non-coding RNA, ribozymes, analogs and derivatives thereof, and combinations thereof. 18. The conjugate of claim 13, wherein the molecule-polymer conjugate has: an in vivo half-life that is at least 25% greater compared with the in vivo half-life of the molecule itself; or an in vivo biodistribution to a tissue, organ, or disease site that is at least 25% greater than the in vivo biodistribution of the molecule itself; or a reduced binding to anti-PEG antibodies compared to a control; or a reduced immune response compared to a control; or a combination thereof. 19. The conjugate of claim 17, wherein the molecule comprises exendin. 20. The conjugate of claim 13, wherein the molecule comprises exendin and each side chain of POEGMA comprises 3 monomers ethylene glycol (EG) repeated in tandem. 21. The conjugate of claim 13, wherein the molecule comprises exendin and each side chain of POEGMA comprises 9 monomers ethylene glycol (EG) repeated in tandem.

Details for Patent 10,364,451

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	January 15, 1974		2033-05-30
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	December 27, 1984		2033-05-30
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	February 15, 1985		2033-05-30
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	February 16, 1990		2033-05-30
Bel-mar Laboratories, Inc.	CHORIONIC GONADOTROPIN	chorionic gonadotropin	Injection	017054	March 26, 1974		2033-05-30