CN1375502A - Polyglycol modified recombinant human interferon - Google Patents
Polyglycol modified recombinant human interferon Download PDFInfo
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- CN1375502A CN1375502A CN 01134085 CN01134085A CN1375502A CN 1375502 A CN1375502 A CN 1375502A CN 01134085 CN01134085 CN 01134085 CN 01134085 A CN01134085 A CN 01134085A CN 1375502 A CN1375502 A CN 1375502A
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- interferon alpha
- recombinant human
- human interferon
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Abstract
The recombinant human interferon modified by polyethylene glycol is characterized by that on the recombinant human interferon one or two or more than two polyethylene glycol chains can be connected, said recombinant human interferon can be interferon alpha 2b, and the average degree of polymerization of said polyethylene glycol chain is 45-230. Said invented recombinant human interferon has the physiological activity of the interferon, and its stability is superior to that of interferon, its plasma clearance is low, the half-life period in vivo is long, it can be used for preparing the medicines for resisting virus and resisting cancer. Said invention also discloses its preparation method.
Description
One, technical field
The present invention relates to a kind of Interferon, rabbit, specifically a kind of polyethyleneglycol modified Interferon, rabbit.
Two, background technology
The security of pharmaceutical grade protein clinical application and validity are the focuses that people pay close attention to and study always.Pharmaceutical grade protein is owing to poor stability, and the transformation period weak point easily produces antigen antibody reaction in the plasma clearance height, body, therefore is very restricted in clinical treatment.Therefore the researchist has adopted various useful for drug delivery technology to improve the curative effect of pharmaceutical grade protein, comprise and adopt different route of administration (as oral, intranasal administration, Transdermal absorption), different carriers are (as microballoon, liposome, red corpuscle, monoclonal antibody), different macromolecular materials (as polysaccharide), different pharmaceutical release tech (as controlled release fertilizer technology, prodrug).And study in the useful for drug delivery technology at present is exactly polyoxyethylene glycol [Poly (ethylene glycol) the most widely, PEG] modification technique, this is a kind of new technology that is used to improve pharmacokinetics character in the protein drug body that recent two decades grows up, it with the activated polyglycol molecular linkage to the protein molecule surface, influence proteinic space structure, finally cause the change of the various biochemical properties of protein.Studies confirm that, come the amino-acid residue on modifying protein surface effectively to improve plasma half-life by covalent linkage with PEG, reduce administration number of times, can also reduce proteinic immunogenicity [referring to Katre NV.The conjugation of proteins with polyethylene glycol andother polymers:Altering properties of proteins to enhance theirtherapeutic potential.Adv Drug Delivery Reviews 10.1993:91-114; NucciML, Shorr R, Abuchowshi A.The therapeutic value of poly (ethyleneglycol)-modified proteins.Advanced Drug Delivery Reviews6,1991:133-151; Zalipsky S.Chemistry of polyenthylene glycol conjugateswith biologicallyactive molecules.Advanced Drug Delivery Reviews16,1995:157-182; Inada Y, Furukawa M, Sasaki H et al.Biomedical andbiotechnological applications of PEG-and PM-modified proteins.Focus, 1995; 13:86-91.].
Before 10 years, reorganization IFN-α just is used for the treatment of hairy cell leukemia by the FDA approval, its indication has covered a very big treatment field at present, be mainly used in viral hepatitis, anticancer, acute infectious disease, immunologic hypofunction and IFN clinically and lack the treatment [Hu Tianbing of syndromes, Liang Wensu. the clinical application of Interferon, rabbit. medical Leader, 2000; 19 (1), 71.].But that uses clinically at present produces the shortcoming that the IFN-α 2b that recombinates has transformation period weak point in the body equally by intestinal bacteria, and has antigenicity, and side effect is comparatively obvious.How to obtain the Interferon, rabbit of slowly-releasing, long-acting form, the moving Fang Xue of medicine that improves it is the emphasis of research to improve tolerance and administration convenience degree always.
Most studies is as decorating site with the amino in the peptide molecule at present.The most frequently used method of preparation protein and polyethylene glycol conjugate is to utilize the electrophilic group of PEG activation back formation and the amino on the protein to react, can be on a globulin molecule after the reaction covalently bound several polymkeric substance long-chains, the number of polymkeric substance long-chain depends on the chemical property that can supply bonded number of sites (free amino group and other electrophilic groups), modifier on the protein molecule, the extra proportion of modifier and reaction conditions.The derivative of PEG roughly has virtueization reagent (contain the chlorination aromatic yl group, can react with the nucleophilic group on the protein), acylating reagent (contain acyl group, link to each other by amido bond with protein) or alkanisation reagent (being connected with the amino formation parahelium on the protein).
Three, summary of the invention
The present invention modifies recombinant human interferon alpha 2 with polyethylene glycol long chain.
Concrete technical scheme of the present invention is as follows:
A kind of polyethyleneglycol modified recombinant human interferon alpha 2, it is to be connected with one on the recombinant human interferon alpha 2, perhaps two or more polyglycol chain.Above-mentioned recombinant human interferon alpha 2 can be an interferon alpha 2 b.The mean polymerisation degree n of above-mentioned polyglycol chain is 45-230.
The preparation method of polyethyleneglycol modified recombinant human interferon alpha 2 of the present invention is: in the solution of interferon alpha, add disodium phosphate soln, regulate its pH value to 7.5-9.5, adding carbonic acid mono methoxy polyethylene glycol succinimide ester then reacts under 0-15 ℃, reaction times is no less than 15 minutes, reaction mixture is carried out chromatographic separation, adopt Superdex 75 Highload to prepare the type gel chromatographic columns, moving phase is the phosphate buffered saline buffer that contains NaCl, and chromatographic separation can get the recombinant human interferon alpha 2 and the polyoxyethylene glycol recombinant human interferon alpha 2s of modifying of modified by polyethyleneglycol more.
Scheme：Use?of?SC-mPEG?for?attachment?of?mPEG?to?proteinsmPEG：CH
3O-(CH
2CH
2O)n-CH
2CH
2OH
The purposes of polyethyleneglycol modified recombinant human interferon alpha 2 of the present invention be used to prepare antiviral, cancer therapy drug, and treatment immunologic hypofunction and IFN lack the medicine of syndromes.
Polyethyleneglycol modified recombinant human interferon alpha 2 of the present invention can keep the antiviral activity of Interferon, rabbit substantially, it has thermostability and enzyme stability preferably than the recombinant human interferon alpha 2 of unmodified again simultaneously, its plasma clearance is low, long half time in the body, liver savings ability is strong, therefore as plain medicine such as antiviral, anticancer, it has bigger superiority than the recombinant human interferon alpha 2 of unmodified.The preparation method of polyethyleneglycol modified recombinant human interferon alpha 2 of the present invention, simple.
Four, description of drawings
Fig. 1 is SDS-PAGE electrophoresis detection figure, and wherein 1 is natural interferon; 2 is the standard specimen of protein molecular weight; 3 is the Interferon, rabbit peak; 4 is the mono-modified recombinant human interferon alpha 2 peak of mono methoxy polyethylene glycol; 5 is the mono methoxy polyethylene glycol recombinant human interferon alpha 2 peaks of modifying more.
Fig. 2 is the comparison that the interferon alpha 2 b of interferon alpha 2 b and mono methoxy polyethylene glycol modification distributes in the liver of mouse.
Fig. 3 uses
125The schema of back Interferon, rabbit pharmacokinetics is modified in the research of I labelling method.
Five, embodiment
The preparation of embodiment 1 carbonic acid mono methoxy polyethylene glycol succinimide ester (SC-mpEG)
Take by weighing 6g mono methoxy polyethylene glycol 5000, triphosgene 0.56g is dissolved among toluene 20ml and the methylene dichloride 12ml, dropwise adds anhydrous triethylamine 1ml, and stirring reaction spends the night.Reaction solution is vacuumized, fling to most of solvent, be dissolved in again among toluene 8ml and the methylene dichloride 10ml residue obtained.Add N-Hydroxysuccinimide 0.21g, get triethylamine 0.3ml, with methylene dichloride 3ml dilution, dropwise add in the reaction solution, after continuing to react completely, with reacting liquid filtering and vacuumize, residue obtained being dissolved among 50 ℃ of ethyl acetate 60ml filtered, and the gained crystallization of cooling back is the SC-PEG crude product.With products therefrom with ethyl acetate recrystallization repeatedly.Measure the infrared spectra of product, following characteristic peak is arranged: 1812,1789 (C=O, succinimides); 1742 (C=O, carboxyls); 1114 (CH
2OCH
2).Measure NMR (Nuclear Magnetic Resonance) spectrum (H-NMR, the CDCl of product
3), following characteristic peak is arranged: 4.35 (m, 4H, CH
2OCO
2); 3.55 (s ,～500H, PEG); 2.74 (s, 8H, CH
2C=O).
The selection in reaction times: get Interferon, rabbit concentrated solution 1ml (0.9mg/ml), the disodium phosphate soln that adds 0.2M is regulated the pH value to 7.5-8.5, gets 0.2ml and places 4 test tube with ground stoppers respectively.Every test tube adds termination reaction behind SC-PEG reaction 15min, 30min, 1h, the 2h of 0.1mg respectively, carries out the SDS-PAGE electrophoresis.Relatively modification rate is determined the modification condition.The result shows that reacting 15 minutes is that the modification rate is lower, and most of Interferon, rabbit is not modified, and the modification rate increases when reacting 30 minutes, and product reacted collection of illustrative plates band no significant difference 1-2 hour to modify the Interferon, rabbit of one and two chain.
The selection of pH value in reaction: get Interferon, rabbit concentrated solution 1ml (0.9mg/ml), respectively get 0.2ml and place 3 test tube with ground stoppers respectively, the disodium phosphate soln that adds 0.2M is regulated pH value to 7.5,8.5,9.5, every test tube adds termination reaction behind the SC-PEG reaction 1h of 0.1mg respectively, detects with HPLC.Determine the pH value of modification reaction.The result shows that the modification rate is low excessively when pH is 7.5, and most of Interferon, rabbit is not modified, and modifies during pH9.5 excessively, and is more more than the modified outcome of two chains, and heterogeneity, is unfavorable for keeping the activity of Interferon, rabbit.
The separation and purification and the evaluation of embodiment 3 modified outcomes
Get interferon alpha 2 b stoste 50ml (0.09mg/ml), its pH value is transferred to 8.5, add SC-mPEG solid 80mg again, dissolving, mixing in 4 ℃ of reaction 1h, adds 2g glycine solid termination reaction.
Get above-mentioned reaction solution 10ml, upper prop separates.Chromatographic condition: Superdex 75 Highload prepare type gel chromatographic columns (26 * 600mm, 22-24 μ m), column volume 320ml, and moving phase is the 0.01M phosphate buffered saline buffer (pH7.18) that contains 0.15M NaCl, flow velocity 1.5ml/min detects wavelength 215nm.Collect each elution peak.The result shows that the elution peak of molecular weight overgauge Interferon, rabbit has two, is respectively mono-modified Interferon, rabbit and many modified interferons.
Each elution peak is suitably concentrated, adopt the SDS-PAGE electrophoresis detection, separation gel 15% concentrates glue 5%.The results are shown in Figure 1, it shows that each separated portion is single band.The antiviral activity mensuration of each component after embodiment 4 modifies [Ministry of Health of the People's Republic of China. one one of Chinese biological goods rules. in 1995 version. Beijing: China Population Press, 1995:268-269.]
Antiviral activity with Wish cell (people's amnion passage cell)-VSV virus (folliculus stomatitis virus) each elution peak of systems measurement.Adopt CPE (cell cause a disease effect) to suppress the inhibition micromethod for the basis, examining the dilution inverse that the high dilution of product still can protect half cell (50%) to avoid virus attack with every milliliter of Interferon, rabbit is Interferon, rabbit unit.Represent with international unit (IU), and proofread and correct with national IFN α standard substance.The results are shown in Table 1.
Tab?1.Antiviral?Activity?of?Conjugates?of?IFNα2b?and?SC-mPEG.
Specific?Activity
Samples
(IU/mg)
Unmodified?IFN 45.5×10
7
α2b
Mono-mPEG-IF 47.4×10
6
Nα2b
Poly- 1.5×10
6
mPEG-IFNα2b
Embodiment 5 modifies the research of back Interferon, rabbit vitro stability
Thermostability: get IFN, mono-mPEG-IFN, each IMIU of poly-mPEG-IFN, place respectively under 4 ℃, 25 ℃, the 37 ℃ conditions, timing sampling is measured the antiviral activity of Interferon, rabbit.The result shows that interferon alpha 2 b is active constant in 37 ℃ of following 2h, and mono-modified interferon alpha 2 b can be kept 90% activity in 4-6h, and many modified interferons α 2b can keep active constant in 4-6h.Interferon alpha 2 b can be active constant in 1 day in the time of 25 ℃, and mono-modified interferon alpha 2 b is in the activity that can keep 90% more than 2 days, and that many modified interferons α 2b can keep in 2-4 days is active constant.It is active constant that interferon alpha 2 b can keep in 4-6 days.And mono-modified interferon alpha 2 b 8-10 days, many modified interferons α 2b18-24 days keeps antiviral activity constant (the aforementioned stable test is in liquid state, do not have carry out under any protectant condition).Therefore, can tentatively think the polyethyleneglycol modified thermostability that can obviously increase interferon alpha 2 b.
Enzyme stability: get 0.1% trypsin solution (pH7.84) 2.7ml, each adds 0.3mlIFN, mono-mPEG-IFN, poly-mPEG-IFN sample, and 25 ℃ of insulations are in 0,20,40,60,90min, 3,4.5, the 6h 0.3ml that takes a sample measures the antiviral activity of Interferon, rabbit.The result shows, interferon alpha 2 b is active in 3-5min to be dropped to originally 50% rapidly, and mono-modified interferon alpha 2 b is at 10-15min, and many modified interferons α 2b is at 15-30min.Therefore, polyethyleneglycol modifiedly can obviously strengthen the ability that interferon alpha 2 b is resisted anti-trypsin hydrolyzing.
Stability in the human serum: the result shows, under 37 ℃.In the interferon alpha 2 b 3h, in the mono-modified interferon alpha 2 b 6h, and in many modified interferons α 2b 12h, keep active constant.
Interferon, rabbit pharmacokinetic after embodiment 6 modifies (
125The I labelling method) significant parameter comprises: (1) transformation period, distribute in (2) body
The calculating of the pharmacokinetic parameter of interferon alpha 2 b and mono-modified interferon alpha 2 b: will
125The Plasma Concentration of the whole blood of I-interferon alpha 2 b with
125After the Plasma Concentration of the whole blood of the mono-modified interferon alpha 2 b of I-is proofreaied and correct.Machine match as calculated, the result meets two chamber models of first order kinetics, i.e. C (t)=Ae
-α t+ Be
-β t, calculate each kinetic parameter (table 2).((D) is linear for AUC and dosage for area under curve.
125The AUC of I-interferon alpha 2 b to the regression equation of dosage D: AUC=-1.003+2.888D (r=0.994, n=3);
125The AUC of the mono-modified interferon alpha 2 b of I-to the regression equation of dosage D: AUC=-0.379+2.212D (r=0.9992, n=3).
Tissue distribution: except kidney (the main metabolic organ of interferon alpha 2 b),
125The distribution ratio of the mono-modified interferon alpha 2 b of I-in other each tissues
125The height of I-interferon alpha 2 b, therefore can think polyethyleneglycol modified can improve the utilization ratio of interferon alpha 2 b in tissue.
125The population distribution of I-interferon alpha 2 b: stomach＞kidney＞lung＞spleen＞liver＞heart＞brain, and
125The population distribution of the mono-modified interferon alpha 2 b of I-: stomach＞liver＞kidney＞spleen＞lung＞heart＞brain.Distribution proportion, particularly polyethylene glycol modified interferon α 2b reduce in the distribution of kidney in the body of polyethyleneglycol modified obvious change interferon alpha 2 b, and increase in the distribution of liver.As can be seen from Figure 2, in different time points
125The mono-modified interferon alpha 2 b of I-(
125I-mono-PEG-IFN α 2b) the distribution of liver apparently higher than
125The I-interferon alpha 2 b (
125I-IFN-α 2b).
125The content of the mono-modified interferon alpha 2 b of I-is 4-10 times of interferon alpha 2 b.
Tab.2?Pharmacokinetic?parmeters?of
125I-IFN-α2b?and?
125I-mono-PEG-IFN-α2b?afteri.v.injection?in?rats(n＝8)
125I-IFNα2b
125I-PEG-IFNα2b
1ug/kg 3ug/kg 5ug/kg 1ug/kg 3ug/kg 5ug/kgA(pg/ml) 48495 6805 21136 37025
8187 24679B(pg/ml) 9087 1250 4124 7911
1231 4158α(h
-1)
16.85 23.47 20.92 20.66
17.14 17.17β(h
-1)
0.9595 0.2545 0.2187 0.2578
0.6811 0.7582k
21(h
-1)
3.35 3.86 3.60 3.85
2.83 3.12
9.63 18.31 16.27 15.69k
12(h
-1) 10.86 10.64 4.83 1.55 1.27 1.38k
10(h
-1) 4.13 4.17 0.0411 0.0295 0.0331 0.0335t
1/2α(h) 0.0404 0.0404 0.665 2.72 3.17 2.69t
1/2β(h) 1.02 0.914 8.39 12.4 11.88 11.13Vc(L/kg) 10.63 10.40 42.24 75.58 68.99 59.58Vd(L/kg) 64.46 57.20 1.381×10
61.932×10
5 6.060×10
5 1.078×10
6 AUC 2.25×10
5 6.918×10
5(pg·h/ml) 0.362 0.518 0.495 0.464CL(ml/h·kg) 0.443 0.433
Embodiment 7
Mono methoxy polyethylene glycol 5000 with mono methoxy polyethylene glycol 2000 or monosubstituted ethoxy cetomacrogol 1000 0 replace among the embodiment 1 obtains the similar result to above embodiment 1-5.
Claims (7)
1. a polyethyleneglycol modified recombinant human interferon alpha 2 is characterized in that being connected with on the recombinant human interferon alpha 2 one, perhaps two or more polyglycol chain.
2. polyethyleneglycol modified recombinant human interferon alpha 2 according to claim 1 is characterized in that recombinant human interferon alpha 2 is an interferon alpha 2 b.
3. polyethyleneglycol modified recombinant human interferon alpha 2 according to claim 1, the mean polymerisation degree n that it is characterized in that polyglycol chain is 45-230.
4. method for preparing the described polyethyleneglycol modified recombinant human interferon alpha 2 of claim 1, it is characterized in that in the solution of interferon alpha, adding alkaline solution, regulate the pH value to 7.5-9.5, add carbonic acid mono methoxy polyethylene glycol succinimide ester then, under 0-15 ℃, react, reaction mixture is carried out chromatographic separation, get the recombinant human interferon alpha 2 and the polyoxyethylene glycol recombinant human interferon alpha 2s of modifying of modified by polyethyleneglycol more.
5. preparation method according to claim 4 is characterized in that the reaction times behind the interferon alpha adding carbonic acid mono methoxy polyglycol succinimide ester is no less than 15 minutes.
6. preparation method according to claim 4 is characterized in that reaction mixture carries out chromatographic separation, and chromatographic condition is to adopt Superdex 75 Highload to prepare the type gel chromatographic columns, and moving phase is the phosphate buffered saline buffer that contains NaCl.
7. the purposes of polyethyleneglycol modified recombinant human interferon alpha 2 according to claim 1 is characterized in that preparing antiviral.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298734C (en) * | 2005-03-25 | 2007-02-07 | 山东格兰百克生物制药有限公司 | Method of modifying protein alpha-amido by carbowax |
| WO2006134497A3 (en) * | 2005-03-09 | 2007-08-30 | Guangwen Wei | Uses of recombinant super-compound interferons |
| US7364724B2 (en) | 2001-02-28 | 2008-04-29 | Sichuan Biotechnology Research Center | Recombinant super-compound interferon |
| US7585647B2 (en) | 2003-08-28 | 2009-09-08 | Guangwen Wei | Nucleic acid encoding recombinant interferon |
| CN111100894A (en) * | 2019-12-31 | 2020-05-05 | 江苏苏南药业实业有限公司 | Method for carrying out fixed-point polyethylene glycol long-acting modification on interferon IFN α -2b |
| US10874716B2 (en) | 2013-01-07 | 2020-12-29 | Superlab Far East Limited | Methods and compositions for treatment of bone, skin, subcutaneous, mucosal and/or submucosal cancer by percutaneous and/or transmucosal administration of interferon |
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2001
- 2001-10-25 CN CN 01134085 patent/CN1375502A/en active Pending
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7364724B2 (en) | 2001-02-28 | 2008-04-29 | Sichuan Biotechnology Research Center | Recombinant super-compound interferon |
| US8114395B2 (en) | 2001-02-28 | 2012-02-14 | Sichuan Biotechnology Research Center | Treatment of viral diseases with recombinant interferon α |
| US8425896B2 (en) | 2001-02-28 | 2013-04-23 | Sichuan Biotechnology Research Center | Treatment of tumors with recombinant interferon alpha |
| US7585647B2 (en) | 2003-08-28 | 2009-09-08 | Guangwen Wei | Nucleic acid encoding recombinant interferon |
| US8287852B2 (en) | 2003-08-28 | 2012-10-16 | Superlab Far East Limited | Treatment of viral diseases with recombinant interferon α |
| WO2006134497A3 (en) * | 2005-03-09 | 2007-08-30 | Guangwen Wei | Uses of recombinant super-compound interferons |
| CN101137391B (en) * | 2005-03-09 | 2012-07-18 | 魏光文 | Uses of recombinant super-compound interferon |
| TWI380993B (en) * | 2005-03-09 | 2013-01-01 | Huiyangtech Usa Inc | Uses of recombinant super-compound interferons |
| CN1298734C (en) * | 2005-03-25 | 2007-02-07 | 山东格兰百克生物制药有限公司 | Method of modifying protein alpha-amido by carbowax |
| US10874716B2 (en) | 2013-01-07 | 2020-12-29 | Superlab Far East Limited | Methods and compositions for treatment of bone, skin, subcutaneous, mucosal and/or submucosal cancer by percutaneous and/or transmucosal administration of interferon |
| CN111100894A (en) * | 2019-12-31 | 2020-05-05 | 江苏苏南药业实业有限公司 | Method for carrying out fixed-point polyethylene glycol long-acting modification on interferon IFN α -2b |
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