CN104744589B - Anti- preS1 antibody, its fusion protein and purposes with interferon - Google Patents
Anti- preS1 antibody, its fusion protein and purposes with interferon Download PDFInfo
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Abstract
The present invention relates to biomedical sector.It specifically, the present invention relates to suppress anti-preS1 antibody, its fusion protein and purposes with IFN of hepatitis B.
Description
Technical field
The present invention relates to biomedical sector.The preS1 that specifically, the present invention relates to suppress hepatitis B resists
Body, itself and interferon（IFN）Fusion protein and purposes.
Background technology
Hepatitis B (Hepatitis B virus, HBV) belongs to hepadnavirus, and infection HBV can not only cause Acute Hepatic
It is scorching, it is also possible to cause chronic hepatitis, hepatic sclerosis even liver cancer.About 2,000,000,000 people once infected HBV in world wide, wherein about
3.5 hundred million people develop into chronic infection due to can not thoroughly remove virus, and the Patients with Chronic HBV Infection for having about 25% can develop into
Liver cancer or hepatic sclerosis( 1 ).Hepatitis B（HBV）Infection is the most common health problem of China.China is HBV infection district occurred frequently, existing
There are infection population 1.3 hundred million, wherein Patients with Chronic HBV Infection 30,000,000, every year because HBV causes direct or indirect economic loss about
900000000000 RMB( 2 )( 3 )。
Hepatitis B surface antigen includes three kinds：Big hepatitis B surface antigen, middle hepatitis B surface antigen and hepatitis B surface antigen, big second
Liver surface antigen includes preS1, preS2 and S areas, and middle hepatitis B surface antigen includes preS2 and S areas, and hepatitis B surface antigen is by S areas
Coding.PreS1 is distributed mainly on on infective virion, is believed to the adhesion of mediate retroviral and target cell.
All hepatitis B virus surface antigen albumen can induce generation neutrality antibody.The generally popular hepatitis B hypotype of China
（Adr and adw）The still unmanned concern of antibody.
HBV infection causes immune tolerance to be that virus is not easy to be eliminated main cause.People are protein induced to various HBV immune
The degree of strength of tolerance is not known.Due to lacking applicable animal model, interacted at present on HBV and host exhausted big
Majority research is carried out by experiment in vitro, and this causes the protein induced Immune escaping mechanisms of HBV and participation induction resistance to
The major viral proteins received（HBsAg,preS1,preS2,HBeAg,HBcAg）It is and indefinite.
At present, for chronic hepatitis B and its treatment means of liver diseases are caused to include：1）For the disease-resistant of HBV
Poison treatment and 2）Liver transplant.Antiviral therapy is to include core for the most basic remedy measures of virus hepatitis, medicine
Viral genome duplication, control can be disturbed or destroyed to glycosides (acid) analog and alpha-interferon (IFN-α) etc., these antiviral drugs
The generation of progeny virus processed, the improvement of liver function can be promoted to a certain extent, regrettably current antiviral therapy can only
By virus control below specified level, it is impossible to thoroughly eradicate virus( 4 )( 5 ).On the other hand, the such medicine of prolonged application there is also
Drawback( 6 ).It for treatment of chronic means is cause China's liver cancer, hepatic sclerosis occurred frequently main to lack effective
Reason.
The immune response power of virus-specific determines final development after infection HBV.Stronger virus-specific
T cell responses and produce anti-HBV envelope proteins antibody and can effectively control virus, cause to infect occur after HBV it is transient,
Self-limited hepatitis, virus are subsequently removed and retain immunological memory.Conversely, weaker or without immune response（Immune tolerance）It is past
It is past directly related with chronic HBV infection( 7 ).Under normal circumstances there is serious T cell functional defect in Patients with Chronic HBV Infection( 8 ).It is long
Time, which receives a large amount of free virus antigenic stimulus, can cause the specific T cell quantity of HBV- to reduce, and the T of virus-specific is thin
Born of the same parents reduce the generation that have impact on special viral antibody again, cause the specific cellular immunities of HBV- and humoral immunity by shadow
Ring.
Anti-HBs antibody neutrality antibody can be spread with blocking virus, accelerate serum-virus to remove and suppress the virus of infection cell
Release, therefore there is potential therapeutic action.But largely free subviral particle in HBV infection person's body be present, weaken significantly
The effect of Anti-HBs antibody neutrality antibody.
The immune response of the normal virus-specific of recombination function is probably to remove virus in Patients with Chronic HBV Infection body
Effective way.Cell caused by HBV infection and humoral immunity tolerance and a large amount of viral antigens being free in blood and liver
Hinder therapeutic vaccine activated immune system.How to break immune tolerance caused by HBV infection and how activated immune system
Construction in a systematic way is stood normally functioning, and stronger, the immune response of virus-specific is the focus and difficult point of HBV therapeutic studies.
We intend developing novel therapeutic strategy and therapeutic vaccine, and substantial amounts of free virus resists in and in Patients with Chronic HBV Infection body
Novel therapeutic vaccine is applied to remove what is had built up on the basis of former and reduction free virus titre and immune tolerance state
Chronic infection.
The surface antigen (HBsAg) of hepatitis B is the main component of serum HBV albumen.PreS1 is the big table of hepatitis B
The sub-fraction of face antigen, it is distributed mainly on on infective virion, ratio is less than total viral particles 1%.We recognize
It is resistant to for break immune may be easier using preS1 as target spot and neutralizes infectious viral particle.Detect preS1 antibody-IFN
Can fusion protein specifically target I types interferon the liver cell of HBV infection, more effectively suppress intracellular virus and answer
System, and break immune is resistant to.We establish various new HBV persistent infection small animal models using viral vector,
Organ, tissue, molecular level analysis HBV how inducing immune tolerance, and analysis the innate immunity and acquired immunity albumen with
The interaction of virus protein.
The content of the invention
In the first aspect, the invention provides specific binding hepatitis B preS1 single-chain antibody（scfv）, its ammonia
Base acid sequence such as SEQ ID NO:Shown in 1, its coding nucleotide sequence such as SEQ ID NO:Shown in 2.Present invention also offers this
The single-chain antibody of invention can be used for detection HBV infection and the propagation for suppressing HBV viruses.In an embodiment
In, single-chain antibody of the invention and human IgG1's Fc amalgamation and expressions.The invention provides the single-chain antibody for expressing the present invention
Expression vector and the host cell for including the expression vector.
In second aspect, the invention provides a kind of fusion protein, it includes and is joined directly together or is connected by connexon
Interferon and the present invention single-chain antibody.In a particular embodiment, interferon and the single-chain antibody of the present invention pass through GS
Connexon connects, and the sequence of connexon is GSSSGSSSGSSS.In a preferred embodiment, fusion protein of the invention includes
Interferon is interferon beta.
At the 3rd aspect, the invention provides specific binding hepatitis B preS1 single-chain antibody（scfv）Or bag
Fusion protein containing interferon and the single-chain antibody is preparing the purposes in being used to treat the reagent of hepatitis B.Specifically,
The invention provides specific binding hepatitis B preS1 single-chain antibody（scfv）Or include interferon and the single-chain antibody
Fusion protein prepare be used for suppress hepatitis B propagation reagent in purposes.
At the 4th aspect, the invention provides the medicine for treating hepatitis B or for suppressing hepatitis B propagation
Composition, it includes the specific binding hepatitis B preS1 of the invention of pharmacy effective dose single-chain antibody（scfv）Or bag
Fusion protein containing interferon and the single-chain antibody, and pharmaceutically acceptable carrier.
Brief description of the drawings
Fig. 1 shows the yeast Yeast-scfv anti-of specific binding PreS1 (adr) albumen filtered out
PreS1 (#61), it is named as pn16-#61.
Fig. 2 shows that the scfvS1 expressed on pn16-#61 and PreS1 (adr) albumen binding affinity are about
78ng/ml。
Fig. 3 shows scfvS1 amino acid sequence SEQ ID NO:1 and coding nucleotide sequence SEQ ID NO:2.
The antibody scfvPreS1-hIgG1Fc of Fig. 4 display present invention can detect preS1 in patients serum, as a result with
The result detected by commercial reagents box matches.
The antibody scfvPreS1-hIgG1Fc of Fig. 5 display present invention combines infected HepG2.215 cell membrane.
The antibody scfvPreS1-hIgG1Fc of Fig. 6 display present invention, which is combined, comes from HBV1.2 and HBV1.3 mouse models
PreS1.
Fig. 7 is shown：The antibody scfvPreS1-hIgG1Fc and mIFNb-scfvPreS1-hIgG1Fc of the present invention makes
HBsAg levels significantly reduce.
Fig. 8 is shown：The antibody scfvPreS1-hIgG1Fc and mIFNb-scfvPreS1-hIgG1Fc of the present invention makes
HBcAg+ cell numbers significantly reduce.
Fig. 9 is shown：MIFNb-scfvPreS1-hIgG1Fc shows the dose-dependent inhibition for HBsAg and HBeAg
Effect.
Figure 10 is shown：MIFNb-scfvPreS1-hIgG1Fc shows the dose dependent thorn for Anti-HBs antibody Ag antibody
Swash effect.
Embodiment
The following examples are only used for further explaining present disclosure, and are not intended to limit this hair in any way
It is bright.Skilled artisans will appreciate that can be modified following embodiments and still without departing from appended claim
The scope, spirit and purport of the present invention for required protection.
In following all embodiments, unless otherwise stated, using the usual used method of those skilled in the art,
Instrument, reagent and experimental program etc..
Embodiment 1：The screening of the anti-preS1 of whole person antibody
1）Growth and induction 109The nonimmune scfv Yeast libraries of diversity people.
2）2 wheel enrichment with magnetic bead are carried out using Miltenyi macs LS posts (Miltenyi#130-042-401).In short
It, by 1010The scfv yeast cells of induction is with biotinylated Antigenic Peptide PreS1 (20~34)-bio (Biotin- of 100mM
) and PreS1 (68~83)-bio (Biotin-TPPHGGLLGWSPQAQG-NH2) [PEPTIDE NPLGFFPDHQLDPAF-NH2
2.0Inc companies] it is being incubated at room temperature 30 minutes, then 5-10 minutes are being incubated on ice.Cell is washed 3 times, is resuspended in cold
In 5ml lavation buffer solutions, and with 200ul Macs Streptavidin MagneSpheres (Miltenyi#130-048-101) or antibiotin
Microballon grain (Miltenyi#130-090-485) is incubated 10 minutes on ice, is gently mixed by being inverted at intervals of two minutes.Will
The Miltenyi macs LS posts that the cell of precipitation is suspended in the cold lavation buffer solutions of 50ml and is loaded into magnetic field
(Miltenyi#130-042-401) post, is washed 3 times with 3ml lavation buffer solutions, the post is taken out from magnetic field, 7ml is added and washes
Buffer solution is washed, all remaining cells are drawn out to collecting pipe using piston.
3）The fluorescent staining of cell from Macs posts and by flow cytometry with regard to antigentic specificity scfv clone into
Row two-wheeled sorts
Most of cell (~5x10 from magnetic posts7Individual cell) with 25nM PreS1 (20~34)-bio/5ul antibody
9E10-647 (anti-myc antibody, 200ug/ml；Make by oneself in this laboratory) double dyeing are carried out, then with Strep-PE
(eBioscience#12-4317-87) dye, first round sorting is carried out with regard to double positive stainings.Double positive colonies are grown and lured
Lead, then with recombinant protein preS1-bio (Shanghai PrimeGene Bio-Tech Co.#672-01；In this laboratory
Carry out biotinylation) and the double dyeing of antibody 9E10-647 progress.Double positive cells are plated on SD+CAAPen/Srep flat boards simultaneously
Single bacterium colony is grown to, each monoclonal then is characterized with regard to the combination situation of itself and Protein PreS1 (adr).As a result：Therefrom select
One shows the clone for having high affinity and selectivity for PreS1 (adr) albumen（Fig. 1）.Yeast Yeast-
Scfv S (anti-preS1) #61 is named as pn16-#61, and the scfv expressed on pn16-#61 surfaces is referred to as
scfvS1.Expression scfv C (anti-HBsAg) yeast is used as negative control.
Use facs analysis method, the average fluorescent strength of the PreS1-bio by determining a series of concentration combined
（MFI）To determine the scfvS1 expressed on yeast pn16-#61 surfaces compatibility.By determining the PreS1- in which kind of concentration
During bio, the scfv expressed on the yeast surface of half determines Kd values with antigen binding.After measured, pn16-#61 surfaces upper table
The scfvS1 reached is about 78ng/ml for PreS1 (adr) binding affinity（Fig. 2）.
Using yeast plasmid Miniprep Kit (Zymo Research#D2001) ferment is extracted from yeast pn16-#61
Matrix grain, it is then transformed into DH5 α competent cells (Invitrogen#18258-012).Use Wizard plus SV
Minipreps DNA purification systems (Promega#A1460) extract DNA from the host from DH5 α, and send to company's survey
Sequence scfv areas.Scfv-PreS1 amino acid sequence and coding nucleotide sequence is shown in Fig. 3.
The secretion and purifying of anti-PreS1 antibody:
Scfv-PreS1 DNA clones are entered into mammalian expression vector pCDNA3.1 (Invitrogen), at its N ends
IgKL has been cloned in end with frame, and hIgG1Fc has been cloned with frame in its C-terminal.By recombinant plasmid pCDNA3.1-IgkL-
ScfvPreS1-hIgG1Fc transfections enter Chinese hamster ovary celI, are divided by the screening of elisa assay method from Chinese hamster ovary celI culture supernatants
The antibody scfvPreS1-hIgG1Fc secreted.By albumin A affinity column from supernatant antibody purification scfvPreS1-hIgG1Fc.
Embodiment 2：Use the preS1 in the scfvPreS1-hIgG1Fc detection patients of the present invention
In order to determine whether scfvPreS1-hIgG1Fc can combine the preS1 from HBV patient, with 50 μ l4ug/ml
Goat anti-human Ig (Jackson ImmunoResearch#109-005-098) coat 96 orifice plates to capture scfvPreS1-
hIgG1Fc.The 50 μ l culture supernatants from embodiment 1 for containing 264ng/ml scfvPreS1-hIgG1Fc are added every
In individual hole.By adding HBsAg shown in Fig. 4+The serum of patient, 20ul/ holes (1:2.5 dilutions).Add 50 μ l Anti-HBs antibodies-HRP
（As capture and detection antibody）（Shanghai KEHUA Bio-Engineering CO, pre-S 1 antigens of hepatitis B viruses detection examination
Agent box）To form Ag-Ab-multienzyme complex.50 μ lTMB substrates are added to be developed and read OD 692 (Fig. 4).As a result
Show that scfvPreS1-hIgG1Fc can detect the preS1 in patients serum, with the result detected by commercial reagents box
Match somebody with somebody.
Embodiment 3：Antibody scfvPreS1-hIgG1Fc can combine expression HBV human liver cell
HepG2.215 is infected using HBV ayw1.3, metainfective cell can produce and discharge HBV particles.In order to survey
Determine whether scfvPreS1-hIgG1Fc antibody can combine HBV+Cell, use the anti-dye HepG2.215 shown in Fig. 5.Knot
Fruit shows that anti-preS1 antibody scfvPreS1-hIgG1Fc can combine infected HepG2.215 cell membrane, but anti-
HBsAg antibody (the antibody C in figure) is not (Fig. 5) in connection.
Embodiment 4：Antibody scfvPreS1-hIgG1Fc can combine a variety of hypotypes
PreS120-34 regions are highly conserved in several Main Subtypes (adr, adw and ayw).HBV1.2 is adr
Hypotype, HBV1.3 are AAVHBV1.3 ayw hypotypes.Using HBV1.2 or HBV1.3 infection B6 mouse, after infection 1 month from
Infected mouse collects serum.ELISA has been carried out to determine whether scfvPreS1-hIgG1Fc can be used for detection HBV particles.
Fig. 6 is shown：ScfvPreS1-hIgG1Fc is combined with the HBV preS1 of the mouse from HBV1.2 and HBV1.3 infection.This table
Bright antibody scfvPreS1-hIgG1Fc of the invention can combine a variety of hypotypes.
Embodiment 5：ScfvPreS1-hIgG1Fc can remove serum preS1
Anti- pres1-huIg-mIFN preparation
Plasmid pEE12.4-IgkL- during mIFNb clones with 12aa GS connexons are entered described in embodiment 1
Between IgKL and scfvPreS1 in scfvPreS1-hIgG1Fc.The plasmid pEE12.4-IgkL-mIFNb- that will be obtained
GSlinker (GSSSGSSSGSSS)-scfvPreS1-hIgG1Fc transfections enter Chinese hamster ovary celI.Pass through albumin A affinity column purifying point
Secrete obtained restructuring mIFNb-scfvPreS1-hIgG1Fc.
Using the scheme shown in Fig. 7, we have detected whether scfvPreS1-hIgG1Fc can reduce HBsAg.Use
HDI (HBV1.26ug) handles B6 mouse.2 months after processing, anti-pres1-huIg is used（That is antibody scfvPreS1-
hIgG1Fc）20ug, mIFNb-scfvPreS1-hIgG1Fc (i.e. mIFNb-scfvPreS1-hIgG1Fc) 20ug or PBS peritonaeums
Interior injection mouse, blood is taken at the time point shown in Fig. 7.HBsAg is monitored by ELISA.Fig. 7 is shown：The horizontal significantly drops of HBsAg
It is low.Collect the liver of mouse and HBcAg and HBsAg are dyed.Fig. 8 result shows, HBcAg+The number of cell is notable
Reduce.
IFN is by systemic administration to suppress virus multiplication, but high-level toxicity prevents its use.It is contemplated that will
IFN is connected with anti-preS1 antibody can target liver and reduce virus multiplication.Result shown in Fig. 7, Fig. 8 shows, anti-pres1
Antibody and mIFNb-scfvPreS1-hIgG1Fc can substantially reduce HBsAg and HBcAg+The number of cell.
In order to determine whether mIFNb-scfvPreS1-hIgG1Fc can reduce HBsAg, the mIFNb- of various dose is used
ScfvPreS1-hIgG1Fc handles HBV1.2+Mouse.MIFNb-scfvPreS1-hIgG1Fc show for HBsAg and
HBeAg dose-dependent inhibition effect (Fig. 9).In addition, as shown in Figure 10, mIFNb-scfvPreS1-hIgG1Fc is shown
For the dose dependent stimulating effect of Anti-HBs antibody Ag antibody (treatment HBV critical therapeutic scheme).
Bibliography：
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2.Liu,J.;Fan,D.Hepatitis B in China.The Lancet.2007.369:1582–1583.
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with hepatocellular carcinoma].(Translated from kor)Korean J Gastroenterol 55
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strategies to treat chronic HBV infection.(Translated from eng)Expert Rev
Gastroenterol Hepatol3(5):561-569(in eng).
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persistence alters CD8 T-cell immunodominance and tissue distribution and
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(2003).
9.Tamada K,et al.(2000)Modulation of T-cell-mediated immunity in
tumor and graft-versus-host disease models through the LIGHT co-stimulatory
pathway.(Translated from eng)Nat Med 6(3):283-289(in eng).
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specific CD8+T-cell immunity to reject established tumors.(Translated from
eng)Blood 107(4):1342-1351(in eng).
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Claims (12)
1. specifically bind hepatitis B preS1 single-chain antibody（scfv）, it is characterised in that amino acid sequence such as SEQ ID
NO:Shown in 1.
2. the single-chain antibody of claim 1, it is characterised in that with human IgG1's Fc amalgamation and expressions.
3. coding specific binding hepatitis B preS1 single-chain antibody（scfv）Nucleic acid molecules, it is characterised in that nucleotides
Sequence such as SEQ ID NO:Shown in 2.
4. include the expression vector of nucleic acid molecules described in claim 3.
5. host cell, it includes the expression vector described in claim 4.
6. fusion protein, it includes the interferon and the antibody of claim 1 or 2 for being joined directly together or being connected by connexon.
7. the fusion protein of claim 6, wherein the connexon is GS connexons, its sequence is GSSSGSSSGSSS.
8. the fusion protein of claim 6 or 7, wherein the interferon is interferon beta.
9. any one of claim 1-2 single-chain antibody or any one of claim 6-8 fusion protein are being prepared for treating
Purposes in the reagent of hepatitis B.
10. any one of claim 1-2 single-chain antibody or any one of claim 6-8 fusion protein are being prepared for suppressing
Purposes in the reagent of hepatitis B propagation.
11. the single-chain antibody of claim 1 or 2 is preparing the purposes in being used to detect the reagent of HBV infection.
12. the pharmaceutical composition for treating hepatitis B, it includes the single-stranded of any one of the claim 1-2 of pharmacy effective dose
Any one of antibody or claim 6-8 fusion protein, and pharmaceutically acceptable carrier.
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| CN106421774B (en) * | 2016-09-08 | 2019-05-28 | 中国科学院生物物理研究所 | PreS1 is used to prepare hepatitis B vaccine and treats the purposes of chronic hepatitis B |
| CN109593130B (en) * | 2018-12-04 | 2021-09-17 | 中国人民解放军陆军军医大学 | Hepatitis B virus pre-S1 antigen specific single-chain antibody and application thereof |
| CN113876938B (en) * | 2020-07-01 | 2024-04-19 | 中国科学院生物物理研究所 | Construction and application of fusion protein vaccine platform |
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| CN102786592A (en) * | 2011-05-17 | 2012-11-21 | 傅阳心 | Specific HBV antibody |
Non-Patent Citations (3)
| Title |
|---|
| 乙型肝炎病毒PreS1蛋白研究进展;易韬;《四川解剖学杂志》;20130331;第21卷(第1期);28-31 * |
| 单链抗体抑制乙肝病毒的研究;刘伟侠等;《中国生物工程杂志》;20111231;第31卷(第12期);104-108 * |
| 大容量天然人源单链抗体库的构建及抗乙型肝炎病毒PreS1单链抗体的淘选;盛辉等;《吉林大学学报( 医学版)》;20040930;第30卷(第5期);753-755 * |
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