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WO2013029062A1 - Conjugués lambda 1 d'interféron peg, leurs procédés de préparation, compositions pharmaceutiques contenant ces conjugués et leurs procédés de fabrication - Google Patents

Conjugués lambda 1 d'interféron peg, leurs procédés de préparation, compositions pharmaceutiques contenant ces conjugués et leurs procédés de fabrication Download PDF

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WO2013029062A1
WO2013029062A1 PCT/VN2011/000009 VN2011000009W WO2013029062A1 WO 2013029062 A1 WO2013029062 A1 WO 2013029062A1 VN 2011000009 W VN2011000009 W VN 2011000009W WO 2013029062 A1 WO2013029062 A1 WO 2013029062A1
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peg
ιρνλι
conjugates
pharmaceutical composition
conjugate
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Nhan HO
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NANOGEN PHARMACEUTICAL BIOTECHNOLOGY CO Ltd
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NANOGEN PHARMACEUTICAL BIOTECHNOLOGY CO Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • This invention relates to new pegylated derivatives of recombinant human interferon lambda 1 (peg-interferon lambda 1 conjugates, peg-IF i) having increased half-lives in circulation, processes for their preparation, pharmaceutical compositions containing these conjugates and processes for making the same.
  • HCV Hepatitis C virus
  • a-interferons are the therapies of choice for the treatment of chronic HCV infection.
  • a-Interferons can give a persistent response to HCV in approximately 70% of cases, however these interferons cause many side-effects, even in case of peg-interferon alpha. These side-effects can sometimes limit treatment, leaving treatment incomplete.
  • Side-effects include influenza-like symptoms and hematologic effects such as thalassemia and anemia.
  • Interferons are proteins produced by immune cells (leukocytes) in response to viral infection. Interferons are currently used for the treatment of many viral diseases such as hepatitis B, hepatitis C, hepatitis D, condyloma acuminata, lepromatous leprosy, chronic leukaemia, AIDS. Interferons alpha are also effective in reducing malignant tumours and treating Kaposi's sarcoma, melanoma, and renal cell carcinoma. Moreover, alpha-interferons are applicable in prevention and treatment of diseases in cattle and other livestock. For example, alpha-interferons enhance the activity of vaccines used in prophylaxis and treatment of foot and mouth disease and porcine reproductive and respiratory syndrome.
  • bacterial diseases such as respiratory infection, mastitis, bovine salmonellosis, and viral diseases such as blue-ear pig disease (also called porcine reproductive and respiratory syndrome-PRRS), pig diarrhea, influenza, Marek's disease, and Gumboro's disease in domestic birds.
  • viral diseases such as blue-ear pig disease (also called porcine reproductive and respiratory syndrome-PRRS), pig diarrhea, influenza, Marek's disease, and Gumboro's disease in domestic birds.
  • Alpha-interferons have been produced from human cell lines incubated in tissue culture media or leukocytes derived from donors.
  • these methods are time consuming, labor intensive, expensive, and not amenable to large scale manufacturing.
  • IL-29 is a member of the helical cytokine family and is a type III interferon. It is also known as interferon lambda 1 (IFN l) and is highly similar in amino acid sequence to IL-28, the other type III interferon.
  • IFN l interferon lambda 1
  • IL-28 and IL-29 ( ⁇ ) were recently described as members of a new cytokine family that shares with type I interferon (IFN) the same Jak/Stat signaling pathway driving expression of a common set of genes. Accordingly, they have been named IFN . IFNs exhibit several common features with type I IFNs: antiviral activity, antiproliferative activity and in vivo antitumour activity.
  • IFNs bind to a distinct membrane receptor, composed of IFNLR1 and IL10R2. This specific receptor usage suggests that this cytokine family does not merely replicate the type I IFN system and justifies its designation as a separate class, the type III IFN by the nomenclature committee of the International Society of Interferon and Cytokine Research.
  • Interferon alpha-2a (Roferon, Roche) and interferon alpha-2b (Intron A, Schering A G), the two recombinant forms of human interferon alpha used in the treatment of chronic hepatitis B and C, have a serum half-life of less than 12h (McHutchison, et al., Engl. J. Med. 1998, 339, 1485-1492; Glue, et al., Clin. Pharmacol. Ther. 2000, 68, 556-567) and therefore require administration 3 times a week.
  • Interferon beta- lb (Betaseron) are also required to treat the patients of multiple sclerosis (MS). The recommended dosing is subcutaneous injection given every other day.
  • filgrastim granulocyte colony stimulating factor, or G-CSF
  • PEG polyethylene glycol
  • PEG moieties are attached to the protein by first activating the PEG moiety and then reacting it with the side chains of lysine residues and/or the N-terminal amino group on the protein.
  • the most frequently used PEG is monofunctional PEG because this moiety resists cross-linking and aggregation.
  • Davis et al. in U.S. Pat. No. 4, 179,337.
  • PEG-protein conjugates were formed by reacting a biologically active material with a molar excess concentration of a highly activated polymer having a terminal linking group without regard to where the polymer would attach to the protein, and leading to a physiologically active, non-immunogenic, water soluble polypeptide composition.
  • Pegylation of interferons has been reported in U.S. Pat. Nos. 4,766,106 and 4,917,888 which describe inter alia beta interferon conjugated with activated polymers including mPEG-2,4,6-trichloro-S-triazine, mPEG-N- succinimidyl glutarate or mPEG-N-succinimidyl succinate.
  • activated polymers including mPEG-2,4,6-trichloro-S-triazine, mPEG-N- succinimidyl glutarate or mPEG-N-succinimidyl succinate.
  • 5,951,974 describes the conjugation of interferon to a substantially non-antigenic polymer at a histidine site.
  • Another such disclosure in U.S. Pat. No. 5,981,709 describes an alpha interferon-polymer conjugate with a relatively long circulating half-life in vivo.
  • Peg-interferon lambda 1 (peg- ⁇ ) is a pegylated derivative of human recombinant ⁇ (wherein polyethylene glycol is conjugated to the ⁇ molecule) useful in treatment of chronic hepatitis C in adult patients. It bypasses the action of extracellular enzymes and resists filtration in the kidney after injection into the patient's body, therefore its half-life in circulation is extended.
  • conjugates of the invention have a linear PEG chain structure. As compared to unmodified ⁇ (that is, ⁇ not conjugated with PEG), these conjugates have increased circulating half-life and persistence in plasma.
  • the present invention is directed to physiologically active peg- ⁇ conjugates having the formulae: O
  • n is a number of units of ethylene glycol in PEG structure and it is a positive integer selected from any numbers such that the molecular weight of PEG moiety is about 40kDa. The number n is selected in the range from 500 to 550.
  • the PEG chain binds to the ⁇ via an amide bond on a primary amino group of, for example, lysine, or the N-terminal of ⁇ .
  • ⁇ could be a natural or recombinant protein.
  • ⁇ is a human protein derived from any source such as tissues, protein synthesis, or cell culture using natural cells or recombinant cells.
  • ⁇ is a human recombinant protein.
  • the conjugates of the invention have similar effects to those of ⁇ , for example, they may be used as anti-proliferative agents, antiviral agents, or antitumor agents.
  • the conjugates of invention are effective in treatment of hepatitis B and hepatitis C, but they have a longer persistence time in blood than IFN l . Therefore, the present invention also provides pharmaceutical compositions containing the above-mentioned human recombinant peg-IFN l conjugates and processes for making the same to use in treatment of hepatitis B and hepatits C.
  • compositions containing the conjugates of the invention are prepared as sterile lyophilized powders for injection or as solutions for injection in vials or pre-filled syringes. These pharmaceutical compositions can be formulated by way of mixing the conjugates with relevant pharmaceutically acceptable carriers and excipients.
  • the invention provides processes for preparation of human recombinant peg- ⁇ conjugates.
  • human recombinant IFN l is produced by recombinant DNA technology in E.coli, then reacted with a pegylating agent (a-methoxy-ro-(4-nitrophenoxy carbonyl)) polyoxyethylene (PEG-pNC) to produce the peg- ⁇ (linear chain PEG 40kDa conjugated to IFNll).
  • a pegylating agent a-methoxy-ro-(4-nitrophenoxy carbonyl) polyoxyethylene (PEG-pNC)
  • PEG-pNC polyoxyethylene
  • the conjugates of the invention are generated by way of covalently binding Interferon lambda 1 with pre-activated PEG (PEG is activated by substituting the PEG hydroxyl with a link group to create the reaction agent that is (a-methoxy-G)-(4-nitrophenoxy carbonyl)) polyoxyethylene (PEG-pNC) ).
  • PEG is activated by substituting the PEG hydroxyl with a link group to create the reaction agent that is (a-methoxy-G)-(4-nitrophenoxy carbonyl)) polyoxyethylene (PEG-pNC) ).
  • the invention will herein focus on description of manufacturing peg- IFN l conjugates from the step of producing ⁇ material to carrying out the pegylation reaction and processes for purifying and assaying the conjugated products.
  • Figure 1 shows the nucleic acid sequence used to produce human recombinant ⁇ in Nanogen Pharmaceutical Biotechnology Co., Ltd. after this sequence was synthesized and introduced into the expression vector pNanogen 1-IL29.
  • Figure 2 shows the amino acid sequence of human recombinant ⁇ produced by Nanogen Pharmaceutical Biotechnology Co., Ltd.
  • Figure 3 shows plasmid pNanogen 1-IL29 containing the gene encoding human ⁇ (interleukin-29).
  • Figure 4 shows the result of analyzing plasmid pNanogen 1-IL29.
  • Figure 5 shows the result of electrophoresis process for examination of the ability of is. coli containing pNanogen 1-IL29 used to produce ⁇ .
  • Figure 6 shows the spectrum of the salt phase and SDS-PAGE electrophoresis after refolding protein.
  • Figure 7 shows the spectrum and SDS-PAGE electrophoresis after cation 1 phase.
  • Figure 8 shows the spectrum and SDS-PAGE electrophoresis after cation 2 phase.
  • Figure 9 shows the spectrum and SDS-PAGE electrophoresis after gel filtration phase.
  • Figure 10 shows the spectrum of the purification process and SDS-PAGE electrophoresis of peginterferon lambda 1.
  • Figure 11 shows the identification results of ⁇ and peg- ⁇ .
  • Figure 12 shows the Maldi-Tof mass-spectrum of peg- ⁇ produced by Nanogen Pharmaceutical Co., Ltd.
  • the invention includes the following main contents: laboratory work to create a recombinant bacterial strain containing the gene encoding ⁇ , industrial manufacturing of ⁇ , pegylation reaction with ⁇ , purification of the produced peg- ⁇ , assay of the properties and characteristics of peg- IFN l .
  • the industrial production process of IFN l includes the steps of: fermenting the initial material, collecting the solution of crude proteins, and purifying the ⁇ protein.
  • the fermentation process was carried out in a 10 litre fermenting tank containing nutrient medium and production of ⁇ was induced by lactose.
  • the biomass obtained was separated and purified.
  • ⁇ was collected and refined through 4 steps including: refolding the protein, separating the protein by ion exchange chromatography (cation 1 and cation 2), and refining the protein on a gel.
  • the pegylation process is a reaction between linear chain (a-methoxy- ⁇ - (4-nitrophenoxy carbonyl)) polyoxyethylene (PEG-pNC - molecular weigh 40kDa) and ⁇ , the product was purified on HPLC system and tested for quality.
  • Example 1 Process for creation of E. coli strain containing the gene encoding human recombinant interferon lambda 1 ( IFN l)
  • the gene encoding IFN l was artificially synthesized based on the protein sequence data available from NCBI or other medicine databases. This is a novel method which reduces the time required to isolate the gene but still gives a result as accurate as the conventional method.
  • the nucleic acid sequence used to produce ⁇ in Nanogen Pharmaceutical Biotechnology Co., Ltd. is presented in Figure 1 and the amino acid sequence of this protein is presented in Figure 2.
  • the expression vector pNanogen-IL29 (comprising the T7 transcription promoter region, the ⁇ transgene, the T7 reverse priming site, the T7 transcription terminator, the fl origin, the kanamycin resistance gene, and the pUC origin of replication) was specifically designed to enable high expression of the protein and facilitate fermentation for industrial production of a large quantity of ⁇ .
  • Figures 3, 4 show the process for creation of vector pNanogen 1-IL29).
  • Vector pNanogen 1-IL29 was then transferred into an E.coli strain suitable for expression of promoter T7. This strain has a genotype F ompT hsdS B (rB ' mB ' )gal dcm (DE3).
  • the strain containing the IFNll gene was called E.Coli- pNanogenl-IL29. It has the ability to produce higher than lOOmg of IFN l per litre by fermentation (see Figure 5) and was introduced into the original strain bank.
  • Example 2 Process for fermentation of E. coli to produce human recombinant IFmi
  • the fermentation process was carried out in a 140 litres fermentation tank with nutrient medium at a temperature 37 ⁇ 0.5°C, air pressure 0.5m 3 /h, pH 7.0 ⁇ 0.2, stirring rate 300rpm and maintained the pH value between 6.8-7.2 by adding H 3 PO4 or NH 4 OH. After 8 hours (when E. coli grew in log phase is the time that cells develop most strongly), the temperature was cooled to 30 ⁇ 0.5°C and the stirring rate was reduced to 200rpm to start the process for generation of IFN l . The fermentation process was stopped after 4 hours, then centrifuged the cold product at 6000rpm to obtain biomass.
  • the biomass was disrupted in a cell lysis solution (12ml solution per lg wet biomass) by homogenizing in a homogenizing device. The temperature was maintained at 4°C for 1 hour, then the cells were disrupted 2 times by an ultrasonic device. The resulting suspension was centrifuged at 6000rpm for 30 minutes to give a pellet. The pellet was then washed with an inclusion body wash buffer (12ml buffer per lg wet biomass), the resulting suspension was kept at 4°C for 1 hour, then centrifuged twice at 13,000 rpm for 30 minutes to obtain a pellet.
  • the pellet was dissolved in 2M urea solution and incubated ice-cold for 1 hour, the suspension was then centrifuged at 13,000rpm for 30 minutes to give the pellet. The pellet was dissolved in a wash solution and centrifuged at 13,000rpm for 30 minutes to give a resulting pellet. The pellet was then dissolved in 6M Guanidine solution, the suspension was kept ice-cold for 12-16 hours, then centrifuged at 13,000rpm for 30 minutes. The solution containing protein was recovered and purified in next step.
  • Example 3 Process for purification of human recombinant IFN l
  • IFN l was refolded by dissolving the inclusion bodies in refolding solution (25mM Tris buffer, ImM EDTA, 1,2M Guanidine pH 8,2) such that the final concentration of the inclusion bodies were 500 ⁇ g/ml. The mixture was then kept at 2-8°C for 16-24 hours. The resulting mixture was desalted before being subjected to a purification step on a Sephadex G25 column.
  • the salt exchange buffer was phosphate buffer (lOmM, pH 8.0).
  • step “cation 1” said desalted mixture was loaded onto a Sephadex G25 column (this column was prefilled with CM-Sepharose FF gel and equilibrated in lOmM phosphate buffer pH 8.0), the product was eluted using lOmM sodium phosphate + 0,5M NaCl pH 8.0).
  • the resulting protein solution was desalted and chromatographed as above (step “cation 2").
  • the protein solution was then filtered through a gel column to give the product human recombinant IF ,1 with purity higher than 95% (see the spectrum and electrophoresis results in figures 5, 6, 7, 8, 9).
  • the solution containing peg- ⁇ , quenched reagent, and unmodified ⁇ was purified on a cation column (this column was prefilled with Sepharose CM gel and equilibrated in lOmM sodium phosphate pH 6.0), eluted with a solution of lOmM sodium phosphate, 0.5M NaCl pH 6.0.
  • the eluted fractions containing protein were transferred into preservative buffer using a solution of lOmM sodium phosphate pH 6.0. This product was then subjected to a sterile filtration process and stored at -20°C.
  • Figure 10 shows the spectrum of the purification process and SDS-PAGE electrophoresis of ⁇ .
  • the resulting peg- ⁇ had a purity higher than 95% and antiviral EMC activity on Hep-2C cell with ED 50 about 10-50ng/ml (see example 6).
  • the antiviral activity of peg- ⁇ was checked similarly to ⁇ .
  • the experiment was carried out with 5 lots (PIL290010111, PIL290020211, PIL29003031 1, PIL290040411, PIL290050511). Similar results were obtained in all lots, with an ED 50 about 10-50ng/ml (see Table 3).
  • Example 8 Molecular weight of peg-IFN l
  • the MALDI-TOF assay was applied to determine the molecular weight of peg-IFNXl. The result is showed in Figure 12, Nanogen's peg- ⁇ has a molecular weight of appropriate 62kDa.
  • peg-IFNXl The acute toxicity of peg-IFNXl was assessed in Swiss mice and rats. ICR mice and Sprague-Dawley rats were inspected for two weeks and healthy 5 week old animals were chosen for the study. Peg-IFN l was administered at three different dosages (high dose 3mg/kg, medium dose 0.3mg/kg, low dose 0.03mg/kg and the vehicle treatment (phosphate buffer saline, pH 7.2)) by subcutaneous or intraperitoneal injection. Animals were observed for clinical signs, body weight changes, and mortality for 14 days after treatment. At the end of the study, all animals were sacrificed, and their tissues and organs were examined for abnormalities. The results are summarized in table 4.
  • Animals (5 weeks old rats) were administered peg- ⁇ at three different dosages (high dose 3mg/kg, medium dose 0.3mg/kg, low dose 0.03mg/kg) by subcutaneous or intraperitoneal injection once a day for 4 weeks.
  • the rats were examined throughout the study for any clinical and behavioral adverse effects caused by Nanogen's peg- ⁇ administration. After the test period, the survived rats were sacrificed for autopsy and biochemical analyses. Blood samples were also collected from abdominal artery to conduct hematologic tests.
  • Table 6 shows the study method and results.

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Abstract

La présente invention concerne de nouveaux conjugués lambda 1 d'interféron PEG (peg-ΓΡΝλΙ), leurs procédés de préparation, des compositions pharmaceutiques contenant ces conjugués et leurs procédés de fabrication. Ces conjugués possèdent un temps de persistance et des demi-vies dans le sang accrus par rapport à IFNλl et sont efficaces dans le traitement de l'hépatite B et de l'hépatite C.
PCT/VN2011/000009 2011-08-25 2011-11-15 Conjugués lambda 1 d'interféron peg, leurs procédés de préparation, compositions pharmaceutiques contenant ces conjugués et leurs procédés de fabrication Ceased WO2013029062A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070071721A1 (en) * 2002-10-23 2007-03-29 Zymogenetics, Inc. Methods for treating viral infection using il-28 and il-29
US7351689B2 (en) * 2004-07-29 2008-04-01 Zymogenetics, Inc. Use of IL-28 and IL-29 to treat cancer and autoimmune disorders
US7727518B2 (en) * 2003-08-07 2010-06-01 Zymogenetics, Llc Method of using IL-29 cysteine mutant to treat hepatitis C and hepatitis B
US20110165121A1 (en) * 2008-06-05 2011-07-07 Hausman Diana F Use of pegylated type iii interferons for the treatment of hepatitis c

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070071721A1 (en) * 2002-10-23 2007-03-29 Zymogenetics, Inc. Methods for treating viral infection using il-28 and il-29
US7727518B2 (en) * 2003-08-07 2010-06-01 Zymogenetics, Llc Method of using IL-29 cysteine mutant to treat hepatitis C and hepatitis B
US7351689B2 (en) * 2004-07-29 2008-04-01 Zymogenetics, Inc. Use of IL-28 and IL-29 to treat cancer and autoimmune disorders
US20110165121A1 (en) * 2008-06-05 2011-07-07 Hausman Diana F Use of pegylated type iii interferons for the treatment of hepatitis c

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZALIPSKY, S.: "Chemistry of polyethylene glycol conjugates with biologically active molecules", ADV. DRUG. DELIV. REV., vol. 16, no. 2-3, 1995, pages 157 - 182 *

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