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WO1994019007A1 - Compositions proteiques d'inactivation du ribosome presentant une antigenicite reduite - Google Patents

Compositions proteiques d'inactivation du ribosome presentant une antigenicite reduite Download PDF

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Publication number
WO1994019007A1
WO1994019007A1 PCT/US1994/001618 US9401618W WO9419007A1 WO 1994019007 A1 WO1994019007 A1 WO 1994019007A1 US 9401618 W US9401618 W US 9401618W WO 9419007 A1 WO9419007 A1 WO 9419007A1
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WIPO (PCT)
Prior art keywords
polymer
substance
conjugate
trichosanthin
poly
Prior art date
Application number
PCT/US1994/001618
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English (en)
Inventor
Terrace W. Hallahan
Carl W. Gilbert
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Enzon, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Enzon, Inc. filed Critical Enzon, Inc.
Priority to AU62404/94A priority Critical patent/AU6240494A/en
Publication of WO1994019007A1 publication Critical patent/WO1994019007A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/415—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention is directed to substances having ribosome inactivating effects such as that produced by trichosanthin in a substantially non- im unogenic form.
  • Trichosanthin is a plant protein which inhibits protein synthesis via ribosome inactivation. Trichosanthin has an extensive history in oriental medicine and has been shown to have anti-viral activity including activity against the human immunodeficiency virus (HIV) . Trichosanthin formulations to date, however, have had serious shortcomings.
  • the protein often referred to as a ribosome inactivating protein or RIP, is very antigenic, toxic, poorly soluble, and has a short circulating half life in vivo. However, its potential use as a therapeutic agent cannot be ignored. It would be highly desirable to provide ribosome inactivating agents which are more soluble, less antigenic and capable of circulating for longer time periods than trichosanthin.
  • One embodiment of the present invention comprises a modified form of trichosanthin which advantageously has a lower toxicity, increased circulating half life, increased solubility and reduced immunogenicity than heretofore available.
  • This embodiment of the present invention comprises the plant protein trichosanthin which
  • SUBSTITUTESHEET has been modified with a non-antigenic polymer.
  • One preferred embodiment comprises a conjugate of trichosanthin and a poly(al ylene oxide) .
  • Another preferred embodiment comprises a conjugate of trichosanthin and an average of about 3-5 strands of poly(ethylene glycol) (PEG) per trichosanthin molecule. It has been demonstrated that the conjugates are more soluble than their unmodified counterparts yet retain a sufficient amount of ribosome activation activity and circulate for extended time periods in vivo.
  • PEG poly(ethylene glycol)
  • Another embodiment of the present invention comprises a method of modifying a substance having a ribosome inactivating effect such as trichosanthin, in a manner which controls the average number of polymeric strands such as PEG bound to the substance. It has been found that it is desirable to control the degree of protein modification to maximize retention of the ribosome inactivation activity of the conjugate.
  • trichosanthin is reacted with a molar excess of a suitable activated polyalkylene oxide such as methoxypoly(ethylene glycol)-N-succinimidyl carbonate (SC-PEG) under conditions sufficient to effect conjugation while maintaining at least a portion of the original trichosanthin activity.
  • a suitable activated polyalkylene oxide such as methoxypoly(ethylene glycol)-N-succinimidyl carbonate (SC-PEG)
  • SC-PEG methoxypoly(ethylene glycol)-N-succinimidyl carbonate
  • molar excess is meant to indicate the ratio of the number of moles of polymeric reagent to the number of moles of trichosanthin.
  • Trichosanthin is a plant protein having a molecular weight of about 25,000 with 9 lysine residues. It is a single chain ribosome inactivating protein (RIP) (Type I Ribosome inactivating protein) isolated from the root tubers of Trichosanthin kirilowii maxim.
  • RIP single chain ribosome inactivating protein
  • the protein is a specific RNA N-glycosidase, inactivating eukaryotic ribosomes by hydrolyzing the N-C glycosidic bond of adenine 4324 of the 28S rRNA. This cleavage removes the adenine base from the ribose but leaves the phosphodiester bond intact.
  • proteins that catalytically inactivate ribosomes in a manner similar to tricosanthin are widely distributed in plants. They are usually single polypeptide chains with molecular weights near 30,000 and are generally homologous to the A-chain of ricin. Examples include, pokeweed antiviral protein, gelonin, Alpha- and Beta-momorcharin and the sapoins among many others. See, for example, Immunotoxins. Frankel, Ed. 175-209 (1988) . The exact type of substance having the ribosome inhibiting effect is not limited to those substances listed herein. Those of ordinary skill in the art will realize that proteins or other substances having the desired ribosome inactivating effect are understood to be included herein.
  • the substantially non-antigenic polymer substances included in the conjugates are preferably poly(alkylene oxides) .
  • alpha- substituted polyalkylene oxide derivatives such as Cj- , alkyl groups.
  • the non- antigenic material be a monomethyl-substituted PEG homopolymer.
  • Alternative polymers such as other polyethylene glycol homopolymers, polypropylene glycol homopolymers, other alkyl-polyethylene oxides, bis- polyethylene oxides and co-polymers or block co-polymers of poly(alkylene oxides) are also useful. In those aspects of the invention where PEG-based polymers are used, it is preferred that they have molecular weights of from about 200 to about 10,000.
  • Covalent modification of the substance is preferred to provide the hydrolysis-resistant conjugate.
  • the covalent modification reaction includes reacting a substance having the desired activity against ribosomal protein production with a substantially non-antigenic polymer substance under conditions efficient to effect conjugation while maintaining at least a portion of the original activity.
  • the polymers may be activated in order to effect the desired linkage with the protein substance.
  • activation it is understood by those of ordinary skill in the art that the polymer is functionalized to include a desired reactive group. Examples of such activation are disclosed in U.S. patents 4,179,337 and 5,122,614, which are hereby incorporated by reference. In the disclosures of these patents, the hydroxyl end groups of polyalkylene glycols are converted and activated into reactive functional groups.
  • trichosanthin is modified with SC-PEG such as that disclosed in the
  • This particularly preferred activated form of PEG for use in the present invention is poly(ethylene glycol)-N-succinimide carbamate.
  • This activated polymer forms stable, hydrolysis-resistant carbamate (urethane) linkages with amino groups of the protein.
  • Other activated PEG'S such as PEG-isocyanate are also of use.
  • the references incorporated herein describe epsilon amino group modifications of lysine, other conjugation methods are also contemplated. Aspartic, gluta ic and/or arginine or other amino acids as well as carbohydrate modifications where available are also within the scope of the present invention.
  • Covalent linkage by any atom between the protein and polymer is possible.
  • non-covalent conjugation such as lipophilic or hydrophilic interactions are also contemplated.
  • One preferred embodiment of the present invention comprises methods of forming conjugates of trichosanthin or similarly acting proteins and non-antigenic polymers, in a controlled manner which limits the average number of polymer strands linked to about 2-5 per protein.
  • the molar ratio of non-antigenic polymer reagent to trichosanthin is modulated to limit the average number of polymers per trichosanthin molecule.
  • a preferred molar ratio is from about 3-7:1. Controlling this ratio is important in order to balance between loss of ribosome inactivating activity and the desired characteristics of a PEG-modification, i.e. increased serum circulating half life and decreased antigenicity and immunogenicity.
  • commercially available trichosanthin is preferably first dialyzed extensively against an appropriate salt buffer system.
  • trichosanthin can be dialyzed against solutions comprising 50 mM sodium phosphate and
  • the phosphate buffer having a pH of about 7.5 may be replaced with a borate buffer having a pH of about 8.0 - 9.0.
  • an excess amount of pyridoxal phosphate for example a 1-15 fold molar excess, is mixed with the trichosanthin in order to protect the most reactive lysine sites on the protein. Pyridoxal phosphate forms a Shiff-base with reactive lysine residues in a reaction that is freely reversible.
  • the pyridoxal phosphate can be easily removed to deprotect the lysines by simply dialyzing the reaction mixture.
  • the pyridoxal phosphate and trichosanthin are allowed to react, for a sufficient time of about 15 minutes, and preferably for about 10 minutes. This reaction is preferably conducted at moderate temperatures, for example below about 27°C, preferably on ice, to avoid risking damage to the protein.
  • a molar excess of a lysine-modifying non-antigenic polymer such as a poly(alkylene oxide) e.g. a poly(ethylene glycol) , is then added to the trichosanthin/pyridoxal phosphate mixture.
  • the polymeric excess will range from about 3 to about 50 fold molar ratio excess and preferably from about 3 to about 7 fold molar excess of the polymer to the protein.
  • the reaction is preferably carried out at temperatures of from 2 - 10°C.
  • the non-antigenic polymer is allowed to incubate in order to react with the other unprotected lysine sites.
  • the incubation time is dependent upon temperature. For example, a lysine- modifying PEG may be allowed to incubate in an ice bath for a half hour followed by further incubation at room temperature for a half hour. Alternatively, this
  • SUBSTITUTE SHEET incubation could be conducted totally on ice for about two hours. The reaction is then stopped such as by adding a sufficient molar excess of a material which is capable of quickly reacting with the lysine-modifying polymer such as glycine.
  • reaction products are further separated for example, by either gel permeation chromatography or by cation exchange fractionation.
  • cation exchange fractionation can be performed on a column of CM-Sephadex gel which has been equilibrated with about 10 mM sodium phosphate pH 6.0.
  • Alternative cation exchange resins may also be used.
  • the PEG-modified trichosanthin protein is eluted from the gel utilizing the same buffer and a suitable eluant, for example sodium chloride.
  • the elution is preferably performed step-wise.
  • 10 mM sodium phosphate buffers containing 0, 50 and 100 millimoles of sodium chloride are used sequentially as the eluants.
  • the conjugates eluted in the fraction coming off without sodium chloride were extensively modified by the polymer and demonstrated low levels of activity.
  • a desirable fraction can be obtained with the eluant containing about 50 millimoles of sodium chloride.
  • Conjugates of trichosanthin with a sufficient amount of ribosomal inactivation activity having, on the average, about 3-5 strands of PEG have been obtained with this fraction.
  • Essentially unmodified proteins were obtained with the eluant containing 100 millimoles of sodium chloride.
  • the artisan can selectively elute conjugates containing varying amounts of polymer strands attached to the protein.
  • varying the amount of salt in the eluant the artisan can selectively elute conjugates containing varying amounts of polymer strands attached to the protein.
  • they can range from highly modified, relatively low activity conjugates with rather long circulating lives to slightly modified, relatively high activity conjugates with somewhat shorter circulating lives, yet, nonetheless, much longer than unmodified proteins.
  • Another aspect of the present invention provides methods of treatment for Acquired Immunodeficiency Disease Syndrome (AIDS) patients with the human immunodeficiency virus (HIV) .
  • the method includes administering an effective amount of the compositions described herein.
  • the amount of the conjugate used in the method of the present invention will vary somewhat from patient to patient, however, conjugates capable of delivering from about 2 micrograms/kg to about 40 micrograms/kg per day of the protein are contemplated.
  • the optimal dosing of the conjugate can be determined from clinical experience.
  • the conjugates are administered in pharmaceutically acceptable vehicles, such as parenteral solutions or other dosage forms.
  • PEG# An estimate of the number of PEG molecules attached to the protein (PEG#) was made by determining the number of free lysine residues in the conjugate as compared to the unmodified protein using a TNBS assay.
  • the PEG number for the three modification reactions were estimated to be 2.5 for example 1, 4.2 for example 2 and 6.9 for example 3. respectively.
  • the activities of the conjugates vs. an unmodified trichosanthin control in an in vitro protein synthesis inhibition assay are shown in Table I.
  • the PEG conjugates were purified by ion exchange chromatography using CM- Spherodex. The 50 mM NaCl eluate was collected for each sample. The PEG #'s for each example, 2.2, 1.6 and 1.7 respectively, were determined by TNBS assay to be similar to that obtained for examples 1-3, indicating that conjugation is unaffected by the presence or absence of added pyridoxal phosphate.
  • Example 6 2X 0.09 As can be seen in the table, the use of pyridoxal phosphate during conjugation results in much higher activity being retained. For example, the in vitro protein synthesis inhibition activity of example 6, where a 2 fold pyridoxal phosphate excess was included, was more than twice that of example 4 which did not include pyridoxal phosphate.
  • Protein synthesis inhibition assays reported in Table III revealed that PEG-trichosanthin prepared in the presence of a 10-fold excess pyridoxal phosphate, example 9, was 5 times more active than example 7, the conjugate prepared without pyridoxal phosphate. These results were also reflected in an assay for inhibition of HIV replication in an in vitro acute infection system such as that set out in AIDS Research and Human Retroviruses. Volume 6, Number 8 (1990). TABLE III
  • Trichosanthin _ 0.0018

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
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  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Compositions renfermant des substances à effet inactivant du ribosome, comme la trichosanthine en combinaison avec des polymères non antigènes, tels que le poly(éthylène-glycol). Ces compositions sont considérablement moins antigènes que des protéines non modifiées. L'invention porte également sur des méthodes d'obtention de ces nouvelles compositions.
PCT/US1994/001618 1993-02-16 1994-02-14 Compositions proteiques d'inactivation du ribosome presentant une antigenicite reduite WO1994019007A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU62404/94A AU6240494A (en) 1993-02-16 1994-02-14 Ribosome inactivating protein compositions having reduced antigenicity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1772693A 1993-02-16 1993-02-16
US08/017,726 1993-02-16

Publications (1)

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WO1994019007A1 true WO1994019007A1 (fr) 1994-09-01

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0948347A1 (fr) * 1997-07-16 1999-10-13 Sophie Chen Agents antiviraux et antitumoraux
US6576235B1 (en) 1998-08-06 2003-06-10 Mountain View Pharmaceuticals, Inc. PEG-urate oxidase conjugates and use thereof
US6783965B1 (en) 2000-02-10 2004-08-31 Mountain View Pharmaceuticals, Inc. Aggregate-free urate oxidase for preparation of non-immunogenic polymer conjugates
US7056713B1 (en) 1998-08-06 2006-06-06 Duke University Urate oxidase
US7811800B2 (en) 2005-04-11 2010-10-12 Savient Pharmaceuticals, Inc. Variant form of urate oxidase and use thereof
US8148123B2 (en) 2005-04-11 2012-04-03 Savient Pharmaceuticals, Inc. Methods for lowering elevated uric acid levels using intravenous injections of PEG-uricase
US8188224B2 (en) 2005-04-11 2012-05-29 Savient Pharmaceuticals, Inc. Variant forms of urate oxidase and use thereof
US9534013B2 (en) 2006-04-12 2017-01-03 Horizon Pharma Rheumatology Llc Purification of proteins with cationic surfactant
US10139399B2 (en) 2009-06-25 2018-11-27 Horizon Pharma Rheumatology Llc Methods and kits for predicting infusion reaction risk and antibody-mediated loss of response by monitoring serum uric acid during PEGylated uricase therapy
US12269875B2 (en) 2023-08-03 2025-04-08 Jeff R. Peterson Gout flare prevention methods using IL-1BETA blockers

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BIOCHEMISTRY INTERNATIONAL, Volume 25, No. 6, issued December 1991, H.W. YEUNG et al., "Properties of Bromodextran-Trichosanthin: A Comparison with Trichosanthin, an Anti-AIDS Protein", pages 1051-1059. *

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0948347A4 (fr) * 1997-07-16 2000-08-30 Sophie Chen Agents antiviraux et antitumoraux
EP0948347A1 (fr) * 1997-07-16 1999-10-13 Sophie Chen Agents antiviraux et antitumoraux
US8618267B2 (en) 1998-08-06 2013-12-31 Mountain View Pharmaceuticals, Inc. PEG-urate oxidase conjugates and use thereof
US6576235B1 (en) 1998-08-06 2003-06-10 Mountain View Pharmaceuticals, Inc. PEG-urate oxidase conjugates and use thereof
US7056713B1 (en) 1998-08-06 2006-06-06 Duke University Urate oxidase
US7723089B2 (en) 1998-08-06 2010-05-25 Mountain View Pharmaceuticals, Inc. PEG-urate oxidase conjugates and use thereof
US9885024B2 (en) 1998-08-06 2018-02-06 Duke University PEG-urate oxidase conjugates and use thereof
US7927589B2 (en) 1998-08-06 2011-04-19 Mountain View Pharmaceuticals, Inc. PEG-urate oxidase conjugates and use thereof
US7927852B2 (en) 1998-08-06 2011-04-19 Mountain View Pharmaceuticals, Inc. Aggregate-free urate oxidase for preparation of non-immunogenic polymer conjugates
US8921064B2 (en) 1998-08-06 2014-12-30 Mountain View Pharmaceuticals, Inc. Method for purifying urate oxidase tetramers and octamers
US8067553B2 (en) 1998-08-06 2011-11-29 Mountain View Pharmaceuticals, Inc. PEG-urate oxidase conjugates and use thereof
US6783965B1 (en) 2000-02-10 2004-08-31 Mountain View Pharmaceuticals, Inc. Aggregate-free urate oxidase for preparation of non-immunogenic polymer conjugates
US7964381B2 (en) 2005-04-11 2011-06-21 Savient Pharmaceuticals, Inc. Variant form of urate oxidase and use thereof
US9926537B2 (en) 2005-04-11 2018-03-27 Horizon Pharma Rheumatology Llc Variant forms of urate oxidase and use thereof
US8188224B2 (en) 2005-04-11 2012-05-29 Savient Pharmaceuticals, Inc. Variant forms of urate oxidase and use thereof
US8293228B2 (en) 2005-04-11 2012-10-23 Savient Pharmaceuticals Inc. Variant form of urate oxidase and use thereof
US8465735B2 (en) 2005-04-11 2013-06-18 Savient Pharmaceuticals, Inc. Variant form of urate oxidase and use thereof
US8541205B2 (en) 2005-04-11 2013-09-24 Savient Pharmaceuticals, Inc. Variant forms of urate oxidase and use thereof
US8148123B2 (en) 2005-04-11 2012-04-03 Savient Pharmaceuticals, Inc. Methods for lowering elevated uric acid levels using intravenous injections of PEG-uricase
US8034594B2 (en) 2005-04-11 2011-10-11 Savient Pharmaceuticals, Inc. Variant form of urate oxidase and use thereof
US9017980B2 (en) 2005-04-11 2015-04-28 Crealta Pharmaceuticals Llc Variant forms of urate oxidase and use thereof
US11781119B2 (en) 2005-04-11 2023-10-10 Horizon Therapeutics Usa, Inc. Variant forms of urate oxidase and use thereof
US9670467B2 (en) 2005-04-11 2017-06-06 Horizon Pharma Rheumatology Llc Variant forms of urate oxidase and use thereof
US7811800B2 (en) 2005-04-11 2010-10-12 Savient Pharmaceuticals, Inc. Variant form of urate oxidase and use thereof
US9926538B2 (en) 2005-04-11 2018-03-27 Horizon Pharma Rheumatology Llc Variant forms of urate oxidase and use thereof
US8178334B2 (en) 2005-04-11 2012-05-15 Savient Pharmaceuticals, Inc. Variant form of urate oxidase and use thereof
US11345899B2 (en) 2005-04-11 2022-05-31 Horizon Therapeutics Usa, Inc. Variant forms of urate oxidase and use thereof
US10160958B2 (en) 2005-04-11 2018-12-25 Horizon Pharma Rheumatology Llc Variant forms of urate oxidase and use thereof
US10731139B2 (en) 2005-04-11 2020-08-04 Horizon Pharma Rheumatology Llc Variant forms of urate oxidase and use thereof
US9534013B2 (en) 2006-04-12 2017-01-03 Horizon Pharma Rheumatology Llc Purification of proteins with cationic surfactant
US10823727B2 (en) 2009-06-25 2020-11-03 Horizon Pharma Rheumatology Llc Methods and kits for predicting infusion reaction risk and antibody-mediated loss of response by monitoring serum uric acid during pegylated uricase therapy
US10139399B2 (en) 2009-06-25 2018-11-27 Horizon Pharma Rheumatology Llc Methods and kits for predicting infusion reaction risk and antibody-mediated loss of response by monitoring serum uric acid during PEGylated uricase therapy
US11598767B2 (en) 2009-06-25 2023-03-07 Horizon Therapeutics Usa, Inc. Methods and kits for predicting infusion reaction risk and antibody-mediated loss of response by monitoring serum uric acid during pegylated uricase therapy
US11639927B2 (en) 2009-06-25 2023-05-02 Horizon Therapeutics Usa, Inc. Methods and kits for predicting infusion reaction risk and antibody-mediated loss of response by monitoring serum uric acid during PEGylated uricase therapy
US11982670B2 (en) 2009-06-25 2024-05-14 Horizon Therapeutics Usa, Inc. Methods and kits for predicting infusion reaction risk and antibody-mediated loss of response by monitoring serum uric acid during pegylated uricase therapy
US12188927B2 (en) 2009-06-25 2025-01-07 Horizon Therapeutics Usa, Inc. Methods and kits for predicting infusion reaction risk and antibody-mediated loss of response by monitoring serum uric acid during PEGylated uricase therapy
US12269875B2 (en) 2023-08-03 2025-04-08 Jeff R. Peterson Gout flare prevention methods using IL-1BETA blockers

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