CN1985992A - New scheme of combining cell factor fusion protein (IL 2/FC) and compound Chinese medicine 861 for enhancing immune response of HB vaccine and breaking immune tolerance of HBV - Google Patents
New scheme of combining cell factor fusion protein (IL 2/FC) and compound Chinese medicine 861 for enhancing immune response of HB vaccine and breaking immune tolerance of HBV Download PDFInfo
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- CN1985992A CN1985992A CNA2006101697564A CN200610169756A CN1985992A CN 1985992 A CN1985992 A CN 1985992A CN A2006101697564 A CNA2006101697564 A CN A2006101697564A CN 200610169756 A CN200610169756 A CN 200610169756A CN 1985992 A CN1985992 A CN 1985992A
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Abstract
The present invention is a kind of medicine composition comprising cell factor fusion protein (IL-2/Fc) and compound Chinese medicine 861, their medicine composition preparation and kit, and their application as immunity potentiator for strengthening HB vaccine immune response and breaking the immune tolerance of HBV.
Description
Technical field
The present invention relates to the treating hepatitis B field, more specifically, the present invention relates to their drug regimen of a kind of cell factor fusion protein IL-2/Fc and a kind of Chinese medicine compound 861, the pharmaceutical composition and the test kit that contain them, and they are as the application of immunostimulant (particularly strengthening the immunostimulant that the hepatitis B virus immune tolerance was replied and broken to hepatitis b vaccine immune).
Background technology
Hepatitis B is a kind of global infectious disease, and particularly multiple in China, according to the data of World Health Organization (WHO), about 2,000,000,000 people in the whole world once infected HBV, and wherein 3.5 hundred million is the chronic HBV infection person, has every year 1000000 people to die from HBV and infects.Hepatitis B infected rate is 57% in China's population, and the HBsAg positive rate is 9.09%, dies from about 300,000 people of HBV relevant disease every year.Thereby hepatitis B is a kind of to the very big disease of people ' s health harm.Yet, be still so far for the treatment of chronic hepatitis B very difficult, especially following several situations:
1. control for hepatitis B; the protective inoculation of neonate Hepatitis B virus vaccine is very important undoubtedly; but the protective rate of using vaccine blocking-up mother-to-baby transmission at present is 87.8%; that is to say that immunne response (being immunologic escape) does not take place 12.2% vaccinate; do not produce the protectiveness hbv antibody; they still can be infected and even infect other people, and this must manage to solve.
2. the infection of China's hepatitis B mainly is through mother-to-baby transmission, and before 15-20 year, the patient belongs to the immunologic tolerance phase basically, though promptly in the body virus replication is arranged, immunoreation does not take place, and it is often invalid to treat, thereby wherein 90% develops into chronic hepatitis;
3. to be developed to the third phase be the inactivity virus carrier state phase to chronic viral hepatitis B, and this period, virus is low duplicated, and is difficult to remove because body immunity is low, and virus may actively once again again cause that sb.'s illness took a turn for the worse after the several years, and also refractory is treated;
4. existing antiviral therapy effect is limited, and interferon is to the clearance rate of hepatitis B only 30%.Nucleoside analog of Chu Xianing such as lamivudine in recent years, adefovirdipivoxil, LdT or the like all can only suppress virus replication, and can not eliminate the masterplate cccDNA of hepatitis B virus duplication, and therefore virus finally will duplicate once again.
Because cytokine plays very important regulatory role in immunoreation, thereby the immunoreation of using cytokine to be brought out, caused great attention, and obtained the experimental result that gets a good chance of with the enhance immunity inoculation.Yet, use cytokine to reply, and be applied to clinically with enhance immunity, do not obtain substantial, breakthrough progress so far, and the obvious result of a lot of experiment in vitro often is difficult to obtain repetition and checking in vivo.
Trace it to its cause, the plasma circulation half-life that cytokine self is of short duration is critical obstacle.Most cytokines is answered immunostimulation and is secreted and bring into play its regulating action.But their plasma half-life is all very of short duration, and this is that a kind of body is avoided over-drastic immunoreactive protection mechanism from the physiology angle.Be example with interleukin-22 (IL-2) wherein, its body-internal-circulation half-life only is 6.9 minutes.Thereby use biological interleukin-22, and or be re-combined into interleukin-22 in body, be difficult to the effective plasma concentration that reaches stable, do not reach the immunostimulant that the interleukin-22 of expection can mediate and the effect of adjusting yet.
Though the Hepatitis B virus vaccine of using at present inoculation has obtained the effect of tangible prevention hepatitis B propagation.Yet still have 10～20% crowd, fail to produce the efficient immune reaction through immunity inoculation.Be called " immunologic escape ".There is not a kind of effective method can make the crowd of " immunologic escape " produce effective immunoreation at present as yet, thereby makes these Susceptible population can not get immunoprotection.We also are faced with more stern challenge simultaneously, and the crowd who promptly accounts for the total population 5～10% of China and part Asian countries is hepatitis b virus carrier.These patients are the carrier of hepatitis B, also are the disseminators, because of its hepatitis B virus surface antigen test positive, claim " the Australia antigen positive " patient again.Great majority " the Australia antigen positive " patient though carry hepatitis B virus, does not produce the immune response of protectiveness in the body, virus and patient are in the state of a kind of " peaceful coexistence ", also claim immune tolerance state.Hepatitis B virus carriers promptly is the potential source of infection of hepatitis B virus, and simultaneously long-term virus is duplicated in vivo, also causes the necrosis of chronic liver cell inflammation, fibrosis, and causes hepatitis interstitialis chronica and even hepatocarcinoma.Still do not have effective widely used method at present and can break " immunologic tolerance ", activate the immunne response at hepatitis B virus of body protective, while the liver protecting cell and function, thereby can not reach removing virus, the purpose that the patient is fully recovered.
Based on above-mentioned, visible current both at home and abroad to the prevention and the treatment of hepatitis B, a main difficult problem is how to solve hepatitis B infected person's the low or immunologic tolerance of immunne response.
Summary of the invention
At above-mentioned research background; the inventor is through research for many years; invented the interleukin-22 fusion rotein; with it and Chinese medicine compound 861 (new side) use in conjunction; set up a new therapeutic scheme; experimental results show that and to improve humoral immunity of organism, cellular immunization effectively, protect hepatocyte again, to solve the problem that above-mentioned treatment and prevention met with to anti-hepatitis virus.
Therefore, an object of the present invention is to provide a kind of cell factor fusion protein (IL-2/Fc), its aminoacid sequence following (SEQ ID NO.1): (following leukorrhagia line part is IL-2, and remainder is the Fc fragment)
M Y S M Q L A S C V T L T L V L L V N S A P T S S S T S S S T A E A Q Q Q Q Q Q Q Q Q Q Q Q H L E Q L L M D L Q E L L S R M E N Y R N L K L P R M L T F K F Y L P K Q A T E L K D L Q C L E D E L G P L R H V L D L T Q S K S F Q L E D A E N F I S N I R V T V V K L K G S D N T F E C Q F D D E S A T V V D F L R R W I A F C Q S I I S T S P Q D P R G P T I K P C PP C K C P A P N L E G G P S V F I F PP K I K D V L M I S L S P I V T C VV V D V S E D D P D V Q I S W F V NN V E V H T A Q T Q T H R E D Y N ST L R V V S A L P I Q H Q D W M S GK A F A C A V N N K D L P A P I E RT I S K P K G S V R A P Q V Y V L PP P E E E M T K K Q V T L T C M V TD F M P E D I Y V E W T N N G K T EL N Y K N T E P V L D S D G S Y FM Y S K L R V E K K N W V E R N S YS C S V V H E G L H N H H T T K S FS R T P G K
*
Cell factor fusion protein of the present invention (IL-2/Fc) is commercially produced and is sold by U.S. Chimerigen company (http://www.chimerigen.com), can be available from Chimerigen, and USA (article number MF-12002).Perhaps, cell factor fusion protein of the present invention (IL-2/Fc) also can be synthetic by the method for describing in the specific embodiments of the present invention.
Another object of the present invention provides the application of above-mentioned cell factor fusion protein (IL-2/Fc) as immunostimulant, and preferred described immunostimulant is to strengthen the immunostimulant that the hepatitis B virus immune tolerance was replied and broken to hepatitis b vaccine immune.
A further object of the invention provides a kind of drug regimen, and it comprises above-mentioned cell factor fusion protein (IL-2/Fc) and Chinese medicine compound 861 (new side).Described Chinese medicine compound 861 (new side) is a kind of medicine for the treatment of hepatitis B, and this medicine is characterised in that the following component that comprises by weight: Caulis Spatholobi 5-20, artificial cordyceps mycelia 5-15, Pericarpium Citri Reticulatae 5-40, Radix Salviae Miltiorrhizae 20-60, Radix Paeoniae Rubra 5-40, Rhizoma Chuanxiong 10-60, Radix Astragali 15-60, Radix Angelicae Sinensis 5-40, Flos Carthami 5-40, Radix Bupleuri 5-20, Rhizoma Cyperi 2.5-10.
The application that focuses on above-mentioned drug regimen as immunostimulant of the present invention, preferred described immunostimulant are to strengthen the immunostimulant that the hepatitis B virus immune tolerance was replied and broken to hepatitis b vaccine immune.
Particularly, the present invention relates to the following:
1. pharmaceutical composition, it comprises cell factor fusion protein IL-2/Fc and Chinese medicine compound 861 in pharmaceutical carrier.
2. according to above-mentioned 1 pharmaceutical composition, wherein said cell factor fusion protein IL-2/Fc has the aminoacid sequence shown in the SEQ ID NO.1.
3. according to above-mentioned 1 pharmaceutical composition, wherein said Chinese medicine compound 861 is a kind of medicines for the treatment of hepatitis B, and this medicine is characterised in that the following component that comprises by weight: Caulis Spatholobi 5-20, artificial cordyceps mycelia 5-15, Pericarpium Citri Reticulatae 5-40, Radix Salviae Miltiorrhizae 20-60, Radix Paeoniae Rubra 5-40, Rhizoma Chuanxiong 10-60, Radix Astragali 15-60, Radix Angelicae Sinensis 5-40, Flos Carthami 5-40, Radix Bupleuri 5-20, Rhizoma Cyperi 2.5-10.
4. according to any one described pharmaceutical composition of above-mentioned 1-3, it comprises Hepatitis B virus vaccine in addition.
5. according to the application of any one described pharmaceutical composition of above-mentioned 1-3 as immunostimulant, preferred described immunostimulant is to strengthen the immunostimulant that the hepatitis B virus immune tolerance was replied and broken to hepatitis b vaccine immune.
6. test kit, it comprises cell factor fusion protein IL-2/Fc and Chinese medicine compound 861.
7. according to above-mentioned 6 test kit, wherein said cell factor fusion protein IL-2/Fc has the aminoacid sequence shown in the SEQ ID NO.1.
8. according to above-mentioned 6 test kit, wherein said Chinese medicine compound 861 is a kind of medicines for the treatment of hepatitis B, and this medicine is characterised in that the following component that comprises by weight: Caulis Spatholobi 5-20, artificial cordyceps mycelia 5-15, Pericarpium Citri Reticulatae 5-40, Radix Salviae Miltiorrhizae 20-60, Radix Paeoniae Rubra 5-40, Rhizoma Chuanxiong 10-60, Radix Astragali 15-60, Radix Angelicae Sinensis 5-40, Flos Carthami 5-40, Radix Bupleuri 5-20, Rhizoma Cyperi 2.5-10.
9. according to any one described test kit of above-mentioned 6-8, it comprises Hepatitis B virus vaccine in addition.
10. according to any one described test kit of above-mentioned 6-8, it comprises operation instructions in addition, this instructions direct with described cell factor fusion protein IL-2/Fc and Chinese medicine compound 861 administering drug combinations in the patient to strengthen hepatitis b vaccine immune among the patient and reply and to break the hepatitis B virus immune tolerance.
Experimental results show that; use interleukin-22-domain-immunoglobulin fusion proteins of the present invention (IL-2/Fc) and Chinese medicine compound 861 (new side) can strengthen protectiveness body fluid and cell immune response that hepatitis B virus vaccine excites; the liver protecting function makes the crowd of immunity " escape " obtain due immunoprotection.Make hepatitis B virus carriers break tolerance status, reach and remove virus and the purpose of treatment hepatitis B virus.The experimental result of interleukin-22-domain-immunoglobulin fusion proteins and Chinese medicine compound 861 (new side) administering drug combinations is shown in Figure 12-15.
Description of drawings
Figure 1 shows that the structure of IL-2/Fc fusion rotein;
Figure 2 shows that the CTLL-2 analysis of cell proliferation;
Figure 3 shows that the competitive experimental analysis of rIL-2 and IL-2/Fc and IL-2 receptors bind;
Figure 4 shows that (half-life of IL-2/Fc shows that two phases are to composition to the IL-2/Fc circulating half-life after disposable 100 μ gIL-2/Fc fusion rotein intravenous injections, an initial quick removing phase is arranged, approximately be 3.5 hours (Fig. 4, A), following an amortization period slowly, approximately be 25 hours (Fig. 4, B));
Figure 5 shows that the cellulotoxic experiment of complement-mediated;
Figure 6 shows that with the Fc receptors bind and test;
Figure 7 shows that IL-2/Fc strengthens the therapeutic scheme of Hepatitis B virus vaccine inoculation;
Figure 8 shows that IL-2/Fc strengthens the special antibody of antiviral that Hepatitis B virus vaccine excites;
Figure 9 shows that IL-2/Fc increases the virus-specific CD8 that the HBV vaccine causes
+The propagation of T cell (last figure is respectively from left to right: do not accept for the first time and HB immunity inoculation for the second time by the A. mice; B. mice is only accepted HB immunity inoculation for the second time; C. mice is accepted for the first time and HB immunity inoculation for the second time simultaneously; D. mice is accepted HB immunity inoculation and IL-2/Fc treatment for the first time, has accepted HB immunity inoculation for the second time again);
Figure 10 shows that compound recipe 861 improves the generation of mouse anti-HBs behind the HBV vaccine immunities (four curves from top to bottom are respectively successively corresponding to thymosin group, 861 groups of compound recipes, IL-2/Fc group, simple vaccine immunity group);
Figure 11 shows that 861 pairs of active influences of mice CTL of compound recipe (are respectively matched group, vaccine group, 861 compound recipes+vaccine group, thymosin+vaccine group and IL2/Fc+ vaccine group from left to right.In 1 group, three medication groups are compared P all＜0.05 with vaccine group; In 2 groups, three medication groups are compared no difference of science of statistics with vaccine group);
Figure 12 shows that IL-2/Fc and 861 compound recipe use in conjunction experimental program with the antibody response effect of enhancing HBV vaccine;
Figure 13 shows that 861 compound recipes and IL-2/Fc use in conjunction have synergistic function to the HBV vaccine antibody response;
Figure 14 shows that 861 compound recipes and IL-2/Fc use in conjunction have synergistic function to the virus-specific CD8+T cell proliferation that the HBV vaccine causes;
Figure 15 shows that 861 compound recipes and IL-2/Fc use in conjunction have synergistic function to the virus-specific CD4+T cell proliferation that the HBV vaccine causes.
Figure 16 shows that IL-2/Fc antigen-4 fusion protein gene construct sketch map.
The specific embodiment
Hereinafter describe reference example in detail the present invention, described embodiment only is intended as illustrative explanation the present invention, rather than intention limits the scope of the invention.Scope of the present invention is specifically limited by accompanying Claim.
In order to keep all biological activity of interleukin-22, and increase its intravital circulating half-life.We use gene engineering method, interleukin-22 (IL-2) is merged mutually with the immunoglobulin Fc fragment gene, and obtain expressing in mammalian cell, thereby create a kind of novel IL-2/Fc fusion rotein (Fig. 1, the structure of IL-2/Fc fusion rotein).
Building process:
Use synthetic primer, (GenBank accessionnumber, NM008366) clone comes out from ATCC 37553 plasmid templates with the IL-2 cDNA of mice.The N-terminal primer adds Restriction Enzyme point of contact NotI.The terminal primer of C-, affix limiting enzyme point BamHI.(GenBank accession number BC108375) is the mRNA reverse transcription of secreting hybridoma (ATCC HB129) from MIgG2a to mice Fcr2a cDNA.The Fcr2a fragment then by synthetic primer added limitations enzyme action point BamHI in the N-end, XbaI is in the C-end, the clone comes out from Fcr2a cDNA template.The mammalian cell protein expression vector is selected pRC/CMV (Invitrogen San Diego for use, CA, USA), IL-2, Fcr2a correctly translates order clone according to aminoacid, and (building process of recombinant expression plasmid: NotI and XbaI enzyme cutting point are cloned into the pRC/CMV expression plasmid, see accompanying drawing 16 for details among advancing the pRC/CMV expression vector; The IL-2/Fc fusion rotein is to express and the performance biological activity with double chain form).
The transfer vector plasmid that has IL-2/Fc arrives in CHO (Chinese HamsterOrary, the ATCC CCL-6) cell through electrotransfection, selects to pick out fusion rotein high yield cell strain through antibiotics G418.The proteic cell of secretion IL-2/Fc is at the culture fluid that does not contain serum (Invitrogen, Cat
#Carry out incubation growth 12045-076), the IL-2/Fc fusion rotein separates through Protein A affinity chromatographic column (GE Healthcare) purifies, the albumen of purifying, is preserved in-20 ℃ of refrigerators through the filter membrane filtration sterilization of 0.22 μ m then through the dialysed overnight of 1 * PBS.
Experiment showed, all biological activity of IL-2/Fc fusion rotein with IL-2.In the active analysis of the detection IL-2 of classics, fusion rotein IL-2/Fc and recombinant il-2 (rIL-2) (injection recombination human interleukin-2 (
125Ala), Beijing Shuanglu Pharmaceutical Co., Ltd., authentication code S-01-04) the same, the propagation (Fig. 2, CTLL-2 analysis of cell proliferation) of the support dependent CTLL-2 cell of IL-2 (ATCC T1B214) is radioactive
125In the analysis that I discharges, IL-2/Fc has the same with recombinant il-2 and the affinity IL-2 receptors bind (Fig. 3, the experimental analysis of emulative and IL-2 receptors bind).(list of references of said determination, Nature, 1977:268,154-156).IL-2 receptor positive CTLL-2 cell is a receptor combination target cell.The CTLL-2 cell was handled 20 seconds through the RPMI of pH3 (Invitrogen), to remove the IL-2 on the bind receptor.Cell after RPMI (pH7) washes twice with
125(MA) co-cultivation 60 minutes is in 37 ℃ of incubators for Dupont, Boston, and the CTLL-2 cell of radiation sign was cultivated on ice 60 minutes with the rIL-2 or the IL-2/Fc of variable concentrations after washing twice, and supernatant goes to and carries out radioactivity determination in the teat glass for I.And IL-2/Fc keeps immunoglobulin half-life, for the serum half-life particular design that detects fusion rotein a kind of enzyme-linked immune detection method (ELISA), use rat anti-mouse IL-2 monoclonal antibody (18161D, Pharmingen clone R19-15, Pharmingen, San Diego, CA, USA) for detecting second antibody, this ELISA is specific at IL-2/Fc, IL-2 and mIgG2a, can not produce false positive reaction.We can carry out quantitative analysis to the IL-2/Fc concentration in the serum, thereby measure the circulating half-life of IL-2/Fc.Compare with recombinant il-2, its body-internal-circulation half-life prolongs nearly 700 times (Fig. 4, IL-2/Fc circulating half-lifes).
Activating complement reaches and the ability of Fc receptors bind because the Fc section of the immunoglobulin of some hypotype has, so have the potential antibody-mediated cell killing and the cytotoxicity function of activating complement mediation.We take two kinds of schemes to keep the characteristics of Fc long half time, avoid its potential immunological effect function.One is for selecting the immunoglobulin hypotype, and the immunological effect function of its Fc mediation is minimum; It is two for using gene engineering method, replaces activating complement in the Fc section and in conjunction with the function amino acid of Fc receptor.These two kinds of methods can reach the purpose of removing or weakening the immunological effect function of Fc mediation to greatest extent.
Complement-dependent cell dissolubility be through
51Cr discharges and measures, and experiment uses the CTLL-2 cell of IL-2 receptor positive to be target cell, and the CTLL-2 cell handled for 20 seconds through hanging down pH (pH3) RPMI.Be combined in the IL-2 of cell surface with removal.Cell after the RPMI culture fluid is washed with
51Cr co-cultivation 60 minutes in 37 ℃ of incubators (DuPont, Boston, MA),
51Cr radio-labeled CTLL-2 cell adds in the dull and stereotyped culture plate in 96 holes after the RPMI culture fluid cleans twice, and density is 5 * 10
4Cell hole, the IL-2/Fc of the present invention of adding variable concentrations, non-cytolytic IL-2/Fc (IL-2/Fc
-/-, be purchased from chimerigen, USA) or mIgG2a (MO is USA) in 60 minutes on ice for Sigma, St.Louis.Then with the hypotoxicity of dilution in 1: 15 exempt from complement (cedarlane, Hombn, Ontario, Canada) or 1%Nonider P-40 (NP-40) (MO USA) adds in the culture plate for Sigma, St.Louis, cultivates 60 minutes and through shaking slowly through 37 ℃.Centrifugal through 10 minutes 200rpm, the supernatant of 140 μ l sucking-off and going to from each culture hole carrying out in teat glass γ measures.Specific cell dissolubility percentage ratio calculates via following formula: the special molten cell of %=(adding the contrast of the experimental group-Jia complement of complement)/NP-40 organize-only adds the contrast of complement) * 100% (Fig. 5, the cellulotoxic experiment of complement-mediated.NP40:Nonider P-40; IL-2/Fc+C ': IL-2/Fc+ complement; IL-2/Fc
-/-+ C ': IL-2/Fc
-/-+ complement; MIg+C ': mIgG2a+ complement; C ': complement).
For measuring the ability of IL-2/Fc and FcrR1 (high-affinity Fc receptor I) receptors bind, the FcrR1 cDNA (GenBank:X14356) that pcr amplification obtains from genome is cloned into the pRC/CMV expression plasmid between NotI and XbaI enzyme cutting point, enter CHO-K1 cell (ATCC CCL-6) through transfection, Chinese hamster ovary celI is FcrRI and FcrRII and IL-2R (IL-2 receptor) negative cells.FcrR1 expresses positive Chinese hamster ovary celI, and (PBS is after 0.1%FCS and 0.1% Hydrazoic acid,sodium salt (Sigma, St.Louis, MO, USA)) clean, with 10 μ g/ml mIgG2a, IL-2/Fc or IL-2/Fc through the FCM buffer
-/-Mix and put 60 minutes on ice, wash twice through the FCM buffer, again with fluorescently-labeled goat-anti IgGFc antibody (Pharmingen, San Diego, CA, USA) mixing was put 60 minutes on ice, and cell adds 1%Formalin/PBS and carries out facs analysis (BectonDickinson Sam Jose after the FCM buffer is washed twice, CA), complement is in conjunction with relevant Glu
318, Lys
320, Lys
322Function amino acid substitutes with Ala, the Leu that the Fc receptors bind is relevant
235Function amino acid substitutes with Glu.(Fig. 6, IL-2/Fc and the experiment of Fc receptors bind).
So, we to create a kind of long lasting interleukin-22 be the IL-2/Fc fusion rotein.
Embodiment 2.IL-2/Fc strengthens humoral immune reaction and the enhancing that Hepatitis B virus vaccine excites significantlyCD8 at hepatitis B virus
+The cellular immunization of T cell
Reach 20 hours circulating half-life because IL-2/Fc has all biological activity of IL-2 and has, we use IL-2/Fc as body fluid and the cell immune response of immunostimulant with enhancing susceptible immune stimulating.We have at first adopted the scheme of IL-2/Fc fusion rotein lumbar injection.The Balb/c mice (is purchased from Beijing dimension tonneau China Company of Animals Ltd., the quality certification number 0060937) accepted Intradermal hepatitis b vaccine immune inoculation (Hepatitis B Vaccine Prepared From Yeast Recombinanted, be Beijing Tiantan Bio-pharmaceuticals technology company limited product, lot number 20080304, each 1 μ g of the every side groin of every Mus subcutaneous injection, accumulated dose 2 μ g/ are only), from second day beginning, accept once a day lumbar injection IL-2/Fc (be purchased the Chimerigen company from the U.S., article number MF-12002,1 μ g/ are only) totally 28 days.(from the immunity inoculation calculating first time) on the 28th, mice is accepted intraperitoneal Hepatitis B virus vaccine inoculation for the second time (each 1 μ g of the every side groin of every Mus subcutaneous injection, accumulated dose 2 μ g/).Immunity inoculation is after two weeks for the second time, carried out measuring (Fig. 7, IL-2/Fc strengthens the therapeutic scheme of Hepatitis B virus vaccine inoculation) according to this area conventional method to the antibody titer of the serum anti-hepatitis virus of inoculation mice and at the CD4+ of hepatitis B virus, the breeder reaction of CD8+T cell.
Experimental result proves that IL-2/Fc strengthens the humoral immune reaction that Hepatitis B virus vaccine excites significantly.The general vaccine Balb/c mice of inoculation separately only produces faint anti-hepatitis virus IgG, and whole Balb/c mices (n=8) of uniting use Hepatitis B virus vaccine and IL-2/Fc, its anti-hepatitis virus antibody titer is all at 1000～1200 times of (Fig. 8, IL-2/Fc strengthens the special antibody of antiviral that Hepatitis B virus vaccine excites, and matched group is a physiology saline injection group).(the detection method of anti-HBs antibody titer: the about 0.5ml of mice vena orbitalis posterior clump blood sampling, 4 ℃ of refrigerators are placed and are spent the night, next day centrifugal 3500rpm * 5rpm, separation of serum is stored in-20 ℃, during mensuration with 400 times of dilutions of above-mentioned serum: 5 μ l serum add in the 2ml normal saline, the machine of going up behind the mixing is measured, and adopts U.S. Abbott Laboratories detection system to measure).
Use the fluorescently-labeled means of CFSE (Carboxy Fluorescein Diacetate Succinimidyl Easter) to carry out intravital T cell proliferative response and analyze (list of references: WellAD, Audmundsdottir H and Turka LA.Folling the Fate of individual Tcells throughout activiation and clonal expression.J Clin Inves.1998,100:3173-3183).Hepatitis B virus CD4+T and the CD8+T cell of the Balb/c mice of inoculation separately all has the breeder reaction that significantly stimulates at hepatitis B virus.Yet IL-2/Fc and Hepatitis B virus vaccine are united the mice of use, and the breeder reaction of its CD8+T (potential cytotoxic cell) has more obviously further enhancing.
Experimental results show that IL-2/Fc and Hepatitis B virus vaccine unite use and can become Radix Achyranthis Bidentatae, thousand times increase at the humoral response of hepatitis B virus really, and increase the breeder reaction (Fig. 9) of CD8+T cell (being the potential cytotoxic cell of scavenger cell inner virus) significantly at hepatitis B virus.This kind method is not seen side effect, can further develop really, use clinical, so that the crowd of immunity " escape " produces antibody and obtains due immunoprotection.Chinese medicine 861 hereinafter described simultaneously in addition, enhance immunity reaction the liver protecting cell can be applicable to " the Australia antigen positive " patient to break the tolerance status to virus, improves the immunne response ability, reaches and removes virus, and treat hepatitis B infected purpose.
The red stilbene mixture of embodiment 3. Chinese medicine compound (new side) (hereinafter to be referred as compound recipe 861 (new side))
About Chinese medicine 861 old sides referring to list of references 1 and 2.The present invention relates to a kind of improved compound recipe 861 (new side), particularly also can be referring to list of references 3.
1. component content: ten Herba indigoferae Pseudotinctoriae such as Radix Salviae Miltiorrhizae, the Radix Astragali, Cordyceps mycelium, Radix Bupleuri, Radix Paeoniae Rubra, Radix Angelicae Sinensis, Flos Carthami, Rhizoma Cyperi, Pericarpium Citri Reticulatae, Caulis Spatholobi, Rhizoma Chuanxiong.
2. processing technology: processing step such as at first that the crude drug of each single medicinal material is concentrated through extracting, dry, granulation, make granule.Then each granule (is provided by Jiangyin City, Jiangsu Province river, sky pharmaceutical factory or the preparation of Beijing Shouchuang Dadi Pharmaceutical Industry Co., Ltd., it is granule that dosage form is provided) (this compound recipe is that the granule made from above each factory mixes by weight following dosage to be uniformly mixed into compound recipe 861 (new side), be not to fry in shallow oil gained altogether, and old side system fries in shallow oil gained altogether): Caulis Spatholobi 5-20, artificial cordyceps mycelia 5-15, Pericarpium Citri Reticulatae 5-40, Radix Salviae Miltiorrhizae 20-60, Radix Paeoniae Rubra 5-40, Rhizoma Chuanxiong 10-60, Radix Astragali 15-60, Radix Angelicae Sinensis 5-40, Flos Carthami 5-40, Radix Bupleuri 5-20, Rhizoma Cyperi 2.5-10.
Above dosage 861 sides than before have very big reduction, former 861 sides, ten flavor crude drugs amount to 147 grams for every pair, new side system extracts each flavor crude drug separately, be spray dried to granule, return the used crude drug dose of calculation with the yield of every flavor medicine, be mixed in proportion, the last actual extracting crude drug in new side restrains for every pair 74 altogether, fry in shallow oil effect altogether with group's medicine and equate (document 3 sees reference) our granule side of being mixed into that experiment showed.After the experiment proved that again 2/3 of new side equates (data in the document 3 that sees reference) with former 861 sides' anti-hepatic fibrosis effect, thereby reached the effect of the remarkable decrement of the used medical material of new side.
3. quality control: system of sky, Jiangyin City river pharmaceutical factory carries out quality control with high pressure liquid chromatographic analysis, Beijing Shouchuang Dadi Pharmaceutical Industry Co., Ltd. carries out quality control with the infrared spectrum finger printing, thereby has guaranteed the quality and the repeatability of the new side of the red stilbene mixture of the Chinese medicine compound that is mixed and made into.
4. compound recipe 861 (new side) is to the potentiation of body specific humoral immunity: with 5 groups of 50 branches of Balb/c mice.With gene recombinaton Hepatitis B virus vaccine groin subcutaneous injection 2 μ g/ only, the 1st day, the 14th day each notes are once to excite the generation of anti-hepatitis B antibody.In vaccine injection simultaneously, in other 4 groups give compound recipe 861 (new side) respectively (3.15g/kg/ day to calculate suspension, irritate stomach once a day), (U.S. SciClone drugmaker provides Thymosin alpha 1,2 μ g/ only, lumbar injection once a day), interleukin-22 fusion rotein (IL-2/Fc, U.S. Chimerigen company is synthetic, 1 μ g/ only, lumbar injection once a day), the result shows, the antibody titer of each group all than vaccine group merely be evident as height (table 1, Figure 10), illustrate that compound recipe 861 (new side) has the effect of the humoral immunization that further enhancing Hepatitis B virus vaccine excited, its effect is similar with each known immunostimulant.
5. compound recipe 861 (new side) is to the potentiation of body specific cellular immunity: use the Balb/c mice, in the 1st day, 14 days and 28 days respectively three recombinant hepatitis b vaccine subcutaneous injections (vaccine is Beijing Tiantan Bio-pharmaceuticals technology company limited product, each 1 μ g of the every side groin of every Mus subcutaneous injection, accumulated dose 2 μ g/ only), again through two week back execution mices, prepare hepatitis B specific killing T cell (CTL) action effect cell (preparation method see reference document 4) by spleen and mix with target cell and hatch.Target cell be transfection the HBsAg plasmid mouse hypertrophy cell oncocyte (P815-S) and with
51Cr labelling (be so kind as to give by hepatopathy center doctor You Hong of Beijing Friendship Hospital, contain the antigenic eukaryon expression plasmid of HBV-S).Two kinds of mixing with cells are exhaled and are educated, and discharge after destroying with target cell
51The activity of the radiocounting of Cr (CPM) sign CTL (detection method see reference document 4), the result shows, compound recipe 861 (newly square) is that (27.3%vs 11.9% for height to the normal P815 cell of kill rate (being that preserve at Beijing Friendship Hospital hepatopathy center) of P815-S, P＜0.05), illustrate that compound recipe 861 (new side) has improved the specific killing activity (table 2 of CTL, Figure 11, matched group are normal saline).
Through at random, the clinical research of double blinding, placebo (concrete scheme see reference document 3), take Chinese medicine compound 861 (new side) can: (1) alleviates chronic viral hepatitis B patient liver inflammation and necrosis, and liver function is improved; (2) sternzellen activation in the control liver; (3) obviously reduce hepatic fibrosis; (4) activity of raising serum collagenase, the level (data not shown) of inhibition TIMP-1.
Mice serum resists-change of HBs and the intervention effect of medicine behind table 1 vaccine immunity
| The animal grouping | The example number | Antibody (W4) | Antibody (W6) | Antibody (W8) | Antibody (W11) | Antibody (W14) | Antibody (W17) | Antibody (W20) |
| |
10 10 10 10 | 1.02±0.48 1.21±0.63 1.33±0.91 0.99±0.42 | 1.25±0.32 1.44±0.29 1.67±0.24 ** 1.44±0.22 | 131.53±86.62 237.23±65.12 * 325.71±168.25 * 178.12±78.12 | 250.68±98.70 379.96±78.09 * 510.79±248.14 * 459.67±251.07 | 180.59±59.42 441.19±180.88 ** 521.56±169.60 ** 554.79±244.95 ** | 141.12±56.47 508.06±227.76 ** 608.36±205.18 ** 493.91±294.75 ** | 129.73±59.66 448.26±224.82 ** 582.28±221.62 ** 271.62±202.96 |
Annotate: compare with simple vaccine group
*P＜0.05
*P＜0.01
861 pairs of active influences of mice CTL of table 2 compound recipe
| The animal grouping | The |
1 group of Vs P815-S (%) | 2 groups of Vs P815 (%) |
| The simple vaccine immunity group of |
10 10 10 10 10 | 17.2±3.0 21.7±3.8 27.3±4.1 * 30.0±5.6 * 36.0±6.9 ** | 16.3±2.4 12.3±2.8 ## 11.9±4.2 ## 13.7±6.0 ## 17.2±7.4 ## |
Annotate: compare with simple vaccine immunity group
*P＜0.05
*P＜0.01; With 1 group of comparison
##P＜0.01P815-S: specificity target cell P815: non-specific target cell
More than studies show that; Chinese medicine compound 861 (new side) can strengthen humoral immunization, the cellular immunization of hepatitis B patient; consistent with the effect of aforementioned IL-2/Fc; Chinese medicine compound 861 (new side) can be improved necrosis of liver inflammation and liver function simultaneously, reverses hepatic fibrosis, both can work in coordination with enhance immunity with the IL-2/Fc coupling; reach therapeutic goal; but the liver protecting to reduce because of the contingent hepar damnification to a certain degree of the enhancing of immunological effect, is received the good effect of the combination of Chinese and Western medicine again.
In sum, the fusion rotein (IL-2/Fc) of cytokine interleukin element-2 of the present invention and immunoglobulin Fc section has the affinity with the recombinant il-2 receptors bind, the half-life is obviously prolonged, and have all biological activity of IL-2; IL-2/Fc has significantly strengthened the humoral immune reaction that Hepatitis B virus vaccine excites, and its anti-hepatitis virus antibody titer is all at 1000～1200 times; IL-2/Fc significantly strengthens the cellular immunization at the CD8+T cell of hepatitis B virus.Thereby can be applicable to the hepatitis B virus carrier state, comprise the patient of immune clearance phase and inactivity HBV carrier state phase.
On the other hand, Chinese medicine compound 861 (new side) flavour of a drug are reduced to the 10-11 flavor, use new processing technology, the purified granule of single medicinal material is formulated in the prescription ratio, dosage than before 861 very big minimizing is arranged, through clinical and experiment showed, drug effect and former 861 sides equivalence at least.A new discovery is, experimental results show that 861 (compound recipes) can strengthen the formation of the hepatitis B that Hepatitis B virus vaccine excites, and improve the specific killing activity of hepatitis B specific killing T cell (CTL).Through at random, the clinical research of double blinding, placebo, Chinese medicine compound 861 (compound recipe) can alleviate chronic viral hepatitis B patient liver inflammation and necrosis, improves liver function, obviously reduces hepatic fibrosis.
Therefore, use in conjunction IL-2/Fc and compound recipe 861 (new side), the two synergism is had complementary advantages, and expection can be brought into play the anti-hepatitis B immune of breaking and tolerate simultaneously the liver protecting again, receives the good effect of the combination of Chinese and Western medicine.
The synergistic function of experimental example 4. compound recipes 861 (new side) and IL-2/Fc
For measuring compound recipe 861 (new side) and IL-2/Fc administering drug combinations to strengthening the immunoreactive effect that Hepatitis B virus vaccine excites.We have adopted the oral independent treatment of IL-2 fusion rotein lumbar injection and compound recipe 861 (new side) and the scheme of drug combination.(Beijing dimension tonneau China Company of Animals Ltd. provides to be divided into the Balb/C mice of 3 groups (8 every group), the quality certification number 0060937) accepted Intradermal Hepatitis B virus vaccine inoculation (Hepatitis B Vaccine Prepared From Yeast Recombinanted, be Beijing Tiantan Bio-pharmaceuticals technology company limited product, lot number 20080304, each 1 μ g of the every side groin of every Mus subcutaneous injection, accumulated dose 2 μ g/ are only), the two groups of mices that began from second day are accepted lumbar injection IL-2/Fc (U.S. Chimerigen company synthesizes, and 1 μ g/ is only) totally 7 days once a day.Wherein unite and accept once a day oral administered compound 861 (new side) treatment separately for one group.The 7th day and the 14th day mice are accepted for the second time, (the Hepatitis B Vaccine Prepared From Yeast Recombinanted of abdominal cavity Hepatitis B virus vaccine inoculation for the third time, be Beijing Tiantan Bio-pharmaceuticals technology company limited product, lot number 20080304, every Mus per injection 1 μ g, accumulated dose 3 μ g/ only), week after the immunity inoculation for the third time, (Figure 12,13 have been carried out measuring to the antibody titer of the serum hepatitis B virus of inoculation mice and at the breeder reaction of the CD8+T cell of hepatitis B virus, 14,15).
Experimental result shows, compound recipe 861 (new side) and the humoral immune reaction that the IL-2/Fc use in conjunction excites for the enhancing Hepatitis B virus vaccine, and enhancing has synergistic function at the cell immune response of the CD8+T cell of hepatitis B virus.
List of references
1.WangBE.Jia JD.Treatment of liver fibrosis.Update on HepatobiliaryDiseases.Klumer Acadermic Publisher.London.1996：193-211
2. the section clock is flat, Wang Baoen, and Wang Tailing, etc.The clinical research of compound recipe 861 treatments and reverse liver fibrosis.China's hepatopathy magazine, 1999,7 (1)
3. open the good fortune Kui, Wang Baoen, Wang Tailing, etc.Compound recipe 861 different preparations compare combination of Chinese and Western medicine hepatopathy magazine, 2000,10 (2): 15-16 to the curative effect of experimental hepatic fibrosis
4. open the chief editor that divides field equally, the modern pharmacology experimental technique.Combined publication society of China Concord Medical Science University of Beijing Medical University, 1997
Sequence table
＜110〉Yanhuang Qiling Biological Sci-Tech Co., Ltd., Beijing
＜120〉cell factor fusion protein (IL-2/Fc) Combined with Chinese Herbal compound recipe 861 strengthens hepatitis b vaccine immune
Reply and break new departure of hepatitis B virus immune tolerance
<130>IB067980
<160>1
<170>PatentIn version 3.1
<210>1
<211>402
<212>PRT
＜213〉artificial sequence
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Met Tyr Ser Met Gln Leu Ala Ser Cys Val Thr Leu Thr Leu Val Leu
1 5 10 15
Leu Val Asn Ser Ala Pro Thr Ser Ser Ser Thr Ser Ser Ser Thr Ala
20 25 30
Glu Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln His Leu
35 40 45
Glu Gln Leu Leu Met Asp Leu Gln Glu Leu Leu Ser Arg Met Glu Asn
50 55 60
Tyr Arg Asn Leu Lys Leu Pro Arg Met Leu Thr Phe Lys Phe Tyr Leu
65 70 75 80
Pro Lys Gln Ala Thr Glu Leu Lys Asp Leu Gln Cys Leu Glu Asp Glu
85 90 95
Leu Gly Pro Leu Arg His Val Leu Asp Leu Thr Gln Ser Lys Ser Phe
100 105 110
Gln Leu Glu Asp Ala Glu Asn Phe Ile Ser Asn Ile Arg Val Thr Val
115 120 125
Val Lys Leu Lys Gly Ser Asp Asn Thr Phe Glu Cys Gln Phe Asp Asp
130 135 140
Glu Ser Ala Thr Val Val Asp Phe Leu Arg Arg Trp Ile Ala Phe Cys
145 150 155 160
Gln Ser Ile Ile Ser Thr Ser Pro Gln Asp Pro Arg Gly Pro Thr Ile
165 170 175
Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Glu Gly Gly
180 185 190
Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile
195 200 205
Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp
210 215 220
Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His
225 230 235 240
Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg
245 250 255
Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys
260 265 270
Ala Phe Ala Cys Ala Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu
275 280 285
Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr
290 295 300
Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu
305 310 315 320
Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp
325 330 335
Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val
340 345 350
Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu
355 360 365
Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His
370 375 380
Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro
385 390 395 400
Gly Lys
Claims (10)
1. pharmaceutical composition, it comprises cell factor fusion protein IL-2/Fc and Chinese medicine compound 861 in pharmaceutical carrier.
2. according to the pharmaceutical composition of claim 1, wherein said cell factor fusion protein IL-2/Fc has the aminoacid sequence shown in the SEQ ID NO.1.
3. according to the pharmaceutical composition of claim 1, wherein said Chinese medicine compound 861 is a kind of medicines for the treatment of hepatitis B, and this medicine is characterised in that the following component that comprises by weight: Caulis Spatholobi 5-20, artificial cordyceps mycelia 5-15, Pericarpium Citri Reticulatae 5-40, Radix Salviae Miltiorrhizae 20-60, Radix Paeoniae Rubra 5-40, Rhizoma Chuanxiong 10-60, Radix Astragali 15-60, Radix Angelicae Sinensis 5-40, Flos Carthami 5-40, Radix Bupleuri 5-20, Rhizoma Cyperi 2.5-10.
4. according to any one described pharmaceutical composition of claim 1-3, it comprises Hepatitis B virus vaccine in addition.
5. according to the application of any one described pharmaceutical composition of claim 1-3 as immunostimulant, preferred described immunostimulant is to strengthen the immunostimulant that the hepatitis B virus immune tolerance was replied and broken to hepatitis b vaccine immune.
6. test kit, it comprises cell factor fusion protein IL-2/Fc and Chinese medicine compound 861.
7. according to the test kit of claim 6, wherein said cell factor fusion protein IL-2/Fc has the aminoacid sequence shown in the SEQ ID NO.1.
8. according to the test kit of claim 6, wherein said Chinese medicine compound 861 is a kind of medicines for the treatment of hepatitis B, and this medicine is characterised in that the following component that comprises by weight: Caulis Spatholobi 5-20, artificial cordyceps mycelia 5-15, Pericarpium Citri Reticulatae 5-40, Radix Salviae Miltiorrhizae 20-60, Radix Paeoniae Rubra 5-40, Rhizoma Chuanxiong 10-60, Radix Astragali 15-60, Radix Angelicae Sinensis 5-40, Flos Carthami 5-40, Radix Bupleuri 5-20, Rhizoma Cyperi 2.5-10.
9. according to any one described test kit of claim 6-8, it comprises Hepatitis B virus vaccine in addition.
10. according to any one described test kit of claim 6-8, it comprises operation instructions in addition, this instructions direct with described cell factor fusion protein IL-2/Fc and Chinese medicine compound 861 administering drug combinations in the patient to strengthen hepatitis b vaccine immune among the patient and reply and to break the hepatitis B virus immune tolerance.
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| Application Number | Priority Date | Filing Date | Title |
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| CN200610169756A CN100586474C (en) | 2006-12-28 | 2006-12-28 | Medicine composition, kit and application thereof |
| PCT/CN2007/003802 WO2008080302A1 (en) | 2006-12-28 | 2007-12-26 | NEW SCHEME OF COMBINING CYTOKINE FUSION PROTEIN (IL-2/Fc) AND TRADITIONAL CHINESE MEDICINE COMPOUND 861 FOR ENHANCING IMMUNE RESPONSE OF HEPATITIS B VACCINE AND BREAKING IMMUNE TOLERANCE OF HEPATITIS B VIRUS |
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| CN1083721C (en) * | 1999-03-29 | 2002-05-01 | 首都医科大学附属北京友谊医院 | Compound Chinese herb medicine for curing fibrosis of liver and hepatocirrhosis and its preparation method |
| US7943146B2 (en) * | 2001-12-21 | 2011-05-17 | Myrexis, Inc. | Immunizing compositions comprising HIV-1 proviral constructs with an inactive p6 gag TSG101 UEV binding domain capable of producing budding-defective viral particles that remain tethered to the cell surface |
| AU2003256678A1 (en) * | 2002-07-19 | 2004-03-03 | Myriad Genetics, Inc. | Method and composition for treating and preventing hepatitis c infection |
| WO2004009032A2 (en) * | 2002-07-19 | 2004-01-29 | Myriad Genetics, Inc | Method and composition for treating and preventing hepatitis b infection and symptoms thereof |
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