CN1448183A - Tumour-curing specific target guiding administration system and use in preparation of tumour-curing medicine - Google Patents
Tumour-curing specific target guiding administration system and use in preparation of tumour-curing medicine Download PDFInfo
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- CN1448183A CN1448183A CN 02105456 CN02105456A CN1448183A CN 1448183 A CN1448183 A CN 1448183A CN 02105456 CN02105456 CN 02105456 CN 02105456 A CN02105456 A CN 02105456A CN 1448183 A CN1448183 A CN 1448183A
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Abstract
The administration system guiding various therapeutic effect agent to tumor cell specifically includes one antibody, one liposome and one joint to connect the antibody and the liposome. Inside the system, the antibody is used in distinguishing and combining with surface antigen of tumor cell, the liposome is used to coat and transport the therapeutic effect agent, and the joint is used to connect the antibody and the liposome. The administration system of the present invention is safe, high in targeting performance, high in guide efficiency and easy to design and synthesize.
Description
Technical field
The present invention relates to a kind of curing specific target guiding administration system, specifically, relate to a kind of drug-supplying system of the tumor cells that various treatment effector agent specificitys can be led.
The invention still further relates to the application of this targeting drug delivery system in preparation medicine for treating tumor thing.
Background technology
At present, along with changes such as the prolongation of human average life and diet, environment, in less than the time in 20 years, China's cancer morbidity has risen 69%, mortality rate has increased by 29.4%, 1997 year about New Development 1,200,000 cancer patient of China, has every year 900000 people to die from cancer approximately, malignant tumor becomes increasingly conspicuous to the mankind's threat, has become one of at present common cause of death.Traditional treatment tumor method comprises that operation, radiotherapy, chemotherapy etc. far can not satisfy numerous cancer patients' requirement, and cancer remains the serious threat of human health.And be the therapy that the Biotherapeutics of representative has become the rich hope of treatment of cancer with gene therapy and immunization therapy.
Cancer is exactly a kind of general disease from the beginning, and particularly behind the excision primary lesion, partial recurrence and transfer have at a distance become the main cause that the restriction curative effect improves, and treatment for cancer depends on the control and the removing of small cancer to a great extent.Traditional auxiliary treatment such as chemotherapy, radiotherapy, biotic factor treatment, and at present in the gene therapy of carrying out clinical trial and immunization therapy etc., all non-specificly at tumor cell, owing to lack targeting, cause Normocellular obvious damage.Because of serious toxic and side effects that this damage brought has often limited the use of these methods and giving full play to of curative effect.Therefore press for a kind of guidance quality route of administration of target tumor cell.The route of administration of this targeting not only can reduce even avoid damage that normal cell is brought, and can improve curative effect in the concentration of tumor by local with improving effector.
The targeted therapy of tumor is the optimal route of administration of oncotherapy, promptly by systemic administration and effector agent such as chemotherapeutics, radionuclide, toxin and gene etc. are targeted to tumor focus specifically play a role, and very little to normal tissue injury.Since 1975 successfully set up monoclonal antibody, monoclonal antibody just became the first-selected object of targeted drug targeting moiety.The major issue that the monoclonal antibody targeted drug faces is (that blood vessel becomes silted up is bent, blood flow disorder and organize the hydrostatic pressing height) and complete monoclonal antibody or many-sided reasons such as its Fab segment molecule amount is big, tissue penetration's difference because the kinetic character of tumor blood flow self, and the guidance quality medicine arrives the especially limited amount of solid tumor deep cell of tumor cell.And owing to have an immunogenicity, easily, limited it and used repeatedly, so the miniaturization of antibody and reduced immunogenicity become development trend for the immune system recognition removing.Along with the developing rapidly and the appearance and the development of antibody engineering and display technique of bacteriophage of technique for gene engineering, people bring into use the variable region scFv (being the zone of conjugated antigen) of antibody as targeted molecular over surplus in the of nearly ten year.Single-chain antibody variable region (scFv) is with variable region of heavy chain V with gene engineering method
HWith variable region of light chain V
LThe recombiant protein that is formed by connecting by connection peptides (Linker), it is affine activity of antigen and the specific minimum functional fragment that has kept parental antibody, a little less than having in non-target tissue short a, immunogenicity of holdup time, the tumor penetration power reaches preparation economic dispatch advantage by force, therefore has the important application potentiality in the fields such as specific diagnosis that targeting gives medicine, toxin and radionuclide, targeting gene therapy and tumor.In early days from hybridoma cell strain clone Fv district gene and the scFv that obtains owing to the decline of tiring makes its affinity low than complete antibody.Along with the development of phage display library technology, particularly pass through from big phage library (＞10
9Transformant) scFv that filters out has high-affinity, and its affinity is equivalent to even surpasses the antibody of immunity once more or three immunity generations.But the gene targeting system based on scFv that can find at present all is implemented in scFv the surface of virus, and certainty also be kept away toxic and side effects such as the threat of pathogenic infection of unavoidable viral carrier and inflammatory reaction.Be used for aspect the target administration at scFv, what report was more at present is to make up recombinant single chain antibody mediated immunity toxin, though its tradition have immunogenicity lower, be easy to advantages such as penetrate tissue and higher curative effect, but because it only has single-action valency antigen-binding site, it is gone into born of the same parents and leads lowlyer, and becomes the main cause that limits its curative effect.At present seldom about scFv and chemotherapeutics and the bonded report of radionuclide, there is research to use with medicinal chemical method conjugated such as scFv and amycin, the tumor and enter cell though fusion molecule can lead preferably, it has partly restricted giving full play to of its effect with the dissociation degree and the hydrolysis method of antibody in cellular inclusion and lysosome.
Liposome is a kind of good delivery carrier known today, it can be effectively that treatments such as therapeutic gene, medicine, toxin and radionuclide is required effector parcel and transport, its conevying efficiency height, toxicity is low, if liposome and monoclonal antibody can be combined effectively, then can make up specific targeting drug delivery system.
Summary of the invention
The object of the present invention is to provide a kind of targeting drug delivery system of tumour-specific, it combines monoclonal antibody and liposome, has TS targeting, and high-efficiency low-toxicity.
Another object of the present invention is to provide the application of targeting drug delivery system of the present invention in preparation medicine for treating tumor thing.
According to an aspect of the present invention, the targeting drug delivery system of tumour-specific comprises an antibody, one liposome and one connects the joint of antibody and liposome, in this system, antibody is used to discern and in conjunction with the antigen of tumor cell surface, liposome is used for parcel and transportation treatment effector agent, and joint is used to connect antibody and liposome.
According to a further aspect in the invention, be used to discern and can be any bonded single-chain antibody of antigen that can exist with tumor cell surface in conjunction with the antibody of TCSA, be preferably anticancer embryonal antigen (CEA) antibody, anti-ferrum haemproteins-2 (Her2) antibody, anti-MAG (Myelin-Associated Glycoprotein) antibody, anti-transferrin (TFR) antibody etc., most preferably be anti-transferrin antibody.For the guidance quality that improves medicine and reduce immunogenicity, the variable region scFv that preferably uses single-chain antibody as and the bonded antibody of TCSA.
In accordance with a further aspect of the present invention, liposome can use any liposome that is suitable for packing and transporting the treatment effector, is preferably the liposome of cationic lipid, and these liposomees can be purchased or adopt method known to those skilled in the art synthetic.
According to another aspect of the invention, the application of targeted system of the present invention in preparation medicine for treating tumor thing is provided, targeted system of the present invention can wrap up treatment effectors such as the antioncogene, antisensenucleic acids of various chemotherapeutics, radionuclide, various immunotoxin and therapy of tumor, be prepared into the medicine of treatment tumor, in chemotherapy, radiotherapy and the Biotherapeutics of tumor, play a role.
The present invention will be coupled at the scFv of TSA on the liposome by a special joint, can therapeutic gene, medicine, toxin and radionuclide be imported tumor cell specifically by liposome more conveniently, have the advantage of high efficiency, targeting, hypotoxicity etc., make it become present comparatively ideal targeting drug delivery system.Targeting drug delivery system of the present invention has following advantage:
1. safe, use humanized antibody fragment and liposome, have the struvite and biological harm that toxic and side effects is low and avoided carriers such as use foreign protein and virus to bring.
2. the targeting height at the special administration of tumor cell, does not almost have influence to normal cell.
3. import efficient efficiently.
4. design is convenient economical, is easy to synthesize.Adopt the genetic engineering synthetic antibody to simplify production technology greatly.
5. wide application prospect, the utilization liposome can wrap up easily gene, antisensenucleic acids, chemotherapeutics, toxin and radionuclide,
6. be applicable to the perform the operation Comprehensive Treatment of back prevention of recurrence and late tumor patient of kinds of tumors patient.
The accompanying drawing summary
Fig. 1 is a targeting drug-supplying system connection diagram in one embodiment of the invention;
Fig. 2 is a targeting drug-supplying system connection diagram in another embodiment of the present invention.
The detailed description of invention
The structure of targeting drug delivery system of the present invention is based on the bonded principle of antigen and antibody specific, utilization at the anti-Fv district (anti-TFRscFv) of transferrin TFR with the effector of the liposome tumor cell that leads specifically.Find after deliberation, be in the tumor cell membrane surface abnormalities high expressed transferrin (TFR) of hypermetabolism and positive controls for high proliferation rates, it is all expressed widely in various tumor cells and strengthens, and therefore becomes the ideal factor that makes up targeting antibodies.Use the effect of this heterogenetic antigen monoclonal antibody obviously to be better than using more special tumor antigen monoclonal antibody (as CEA, Her2, MAG etc.), and this guidance system normal structures such as bone marrow, intestinal mucosa that effector do not led are found in experiment, though its reason may be TFR expression is arranged in normal structure, but its expression, often preferentially combines with tumor cell in corresponding antibody enters body well below tumor tissues.The present invention uses the phage display library technology from clone through the transgenic mice of immunity and screen the scFv gene of anti-TFR, and adopts the affinity maturation technology to improve the affinity of antibody.Designed special joint and first scFv antibody has been connected in liposome, can wrap up multiple effector (as gene, chemotherapeutics, radionuclide and toxin etc.) easily, realized target administration by liposome.This system has the following advantages than other guidance system: 1. because the scFv molecule is little, very easily entering interstice with liposome by the tumor blood capillary that permeability increases, is that the immunoliposome of guiding has the higher conveying capacity of organizing with scFv in tumor tissues; 2. the equal non-immunogenicity of the scFv of peopleization and liposome can not limit its repeated use because of produce antibody in body; 3. liposome is more easily gone into born of the same parents by endocytosis or with the cell membrane fusion, in cell the release of medicine easy, and do not exist the antibody coupling medicine to change the problem of medicines structure.4. experiment finds that also TFR-scFv can strengthen the endocytosis of liposome.
Below, in conjunction with the accompanying drawings,, describe the present invention in detail by description to better embodiment of the present invention:
Embodiment 1The preparation of liposome
Cationic lipid [Dioleoy] trimethylammonium propane (DOTAP) anddioleoyl phosphalidylothanolamine (DOPE)] liposome complex press literature method synthetic (Journal fo Controlled Release 61 (1999) 233-240).
Embodiment 2The preparation of single-chain antibody
From through the Fv district of immunity transgenic mice, extracting mRNA, with V district specificity promoter amplification V
HAnd V
LSequence, and improve affinity of antibody with affine mature technology.With V
H, V
LConnect and be cloned into phage vector PCNTAB6 (Pharmacia) with joint, make up scFv antibody gene storehouse.With the antigen coated immune post screening and separating phage antibody library of TFR, the antigenic phage of strong acid elution of bound, infect coliform amplification phage, and through repeatedly screening the TfRscFv that obtains high-affinity.The TFRscFv that modifies through fat on the purification of bacterial film obtains a bioactive molecule, and it can be connected to liposome with the fat label by a kind of embedding.The TFRscFv that fat is modified is isolating from the film of bacterial expression host SFH0F.And by metal integration chromatography purification from the dissolved film of detergent.The basic preparation method of TTRscFv immunoliposome is seen people's such as deKruif description.The TFRscFv one that the fat made from the wafer form (DOTAP/DOPE) and fat are modified reinstates n-octyl group β-D-glucoside dissolving of 1%.
Embodiment 3Antibody is connected with liposome
Referring to Fig. 1 and Fig. 2, the single-chain antibody that more than prepares is connected with joint with liposome, makes up targeting drug delivery system.
Embodiment 4The targeting chemotherapy
The side effect of the cancer therapy drug maximum of clinical use also has lethal effect to normal proliferative cell exactly, and particularly the toxicity to bone marrow, intestinal mucosa, liver and kidney and other organs has usually limited the continuation utilization of chemotherapy even directly brought life danger to patient.Anti-TFRscFv-lipob is with the special guiding tumor cell of medicine in utilization, can obviously improve the tumor by local drug level, reduces drug dose, and experiment finds that bone marrow and intestinal mucosa are not had obvious damage.We have inoculated the tumor-bearing mice of lung carcinoma cell with the treatment of anti-TFRscFv-lipob parcel amycin, the number and the size that found that treatment group mouse lung focus all significantly reduce, 85.9% mice focus complete obiteration, whole mice long-term survivings (170d), and the long-term survivors is not arranged without the contrast treatment group of specificity guiding.Experiment with anti-TfRscFv-lipob parcel daunorubicin has obtained similar results.Our preliminary experimental result shows that this targeted system can obviously strengthen the curative effect of following chemotherapeutics:
Amycin, daunorubicin, benzenebutanoic acid ammonia mustard, methotrexate, 5-fluorouracil, cisplatin, triaziquone, vindesine, left-handed phenyalamine mustard, anthracin, maytansioids, vincristine and B1eomycin.
Embodiment 5Target gene therapy
A large amount of studies show that Normocellular vicious transformation relates to the mutual growth and decline of oncogene and antioncogene, is that abnormal activation and the transition of oncogene expressed on the one hand, is the disappearance or the inactivation of cancer suppressor protein on the other hand.And gene therapy is the Biotherapeutics direction, makes these cell normal growths by quiding gene, and the secretion efficiency factor is to regulate various antitumor immune competent cells or to directly act on cancerous cell or regulate tumor to the sensitivity of other treatment measure as change, radiotherapy.Therapy of tumor clinical experiment effect is undesirable at present, and the problem of most critical is to lack the efficient carrier system with guidance quality.
We use the tumor-bearing mice of anti-TTRscFv-lipo mediation wild type p53 (wtp53) gene transfection treatment carcinoma of prostate, by about 50% tumor cell of intravenous administration transfected (apparently higher than the transfection efficiency of adenovirus wtp53 local injection), cooperate radiotherapy, the experimental mice tumor disappears fully, the whole long term survivals of mice, effect obviously are better than independent radiotherapy and adenovirus mediated wtp53 gene therapy.We use this guidance system transfection wtp53 to treat the 10 invalid advanced lung cancer patients of other Therapeutic Method of example, wherein 1 routine patient's cancer complete obiteration, and 3 routine cancer obviously dwindle, and 4 routine tumor sizes stop development.Curative effect is satisfactory.
We mediate the animal model of co-transfection suicide gene RSV-tk and the hepatic metastases of IL-2 gene therapy colon cancer with anti-TFRscFv-lipo, find that tumor cell gene transfer rate reaches 65%, co-transfection group tumor disappears fully, and the tumor area of transfection IL-2 and RSV-tk is respectively 120mm separately
2And 25mm
2
We also use the Bcl-2 gene therapy advanced NPC of this transfection system mediation antisense construct, the radiotherapy of antisense Bcl-2 gene transfection combination tumor focus, radiotherapy improves effective percentage 30% separately, accept in the case that 26 routine tumors of therapeutic alliance disappear fully so far none example and find tumor recurrence, the longest disease free survival 26 months.Curative effect is very satisfied.
This guidance system can be used to the gene therapy (comprising combined gene therapy) of the following aspects:
1, immune factor system: TNF, IL-2, GM-CSF, IL12 etc.
2, antioncogene: wtp53, Rb, p16, p21 etc.
3, histocompatibility antigen and costimulating factor: as HLA and B7 etc.
4, suicide gene therapy: the sweet kinases HSV-tk of herpes simplex virus breast, cytosine desaminase CD, escherichia coli nitroreductase etc.
5, Antisense gene therapy: as bcl-2, c-myc, k-ras etc.
Embodiment 6The radionuclide targeted therapy
The radioimmunotherapy using specific antibody is brought into play local lethal effect with the radionuclide tumor focus part of leading, and has selective killing and at the advantage of minimal disease, receives much concern always.But there are a plurality of major defects in antibody mediated immunity complex in the past, because complex molecule is bigger, the radionuclide uptake ratio approximately only is 0.001-0.01%ID/g in the big tumor; Antibody combines tightr with nucleic, exist the problem of degraded and dehalogenation behind the born of the same parents; Because inhuman endogenous antibody is used in the body of back and is produced antibody, has limited it and has repeatedly used.Our this guidance system has overcome above-mentioned defective preferably.We wrap up Y with anti-TFRscFvg-lipo
90The tumor-bearing mice of treatment pulmonary carcinoma finds that uptake ratio can reach 1%ID/g in the 3cm size tumor, and these intralesional absorbed dose reach 20000cGy, and average exposure dose is approximately 289cGy/hr.All tumor-bearing mice focuses disappear fully, the long-term disease free survival of mice, and find no obvious toxic-side effects.
The nucleic that is suitable for this system's nucleic targeted therapy comprises:
131I,
125I,
33P,
198Au,
90Y,
188Re etc.
Embodiment 7Be used for the immunotoxin treatment
Immunotoxin has tempting use prospect owing to combine the selectively targeted effect of the cytotoxicity efficiently and the antibody of natural toxin.But conventional method is with toxin and antibody linked, and the often complicated difficulty of cross-linking process needs the middle access bridge of albumin again, and this has just caused many problems: the one, and the biologic activity of antibody and toxin is affected even disappears; The 2nd, cross-linking agent is often unstable, and the holding time is short; The 3rd, the cross-linking agent molecule is relatively large, and application easily is eliminated blood circulation in the body; The 4th, cross-linking agent is to be difficult for purification.These have had a strong impact on the use of cross-linking agent.Our this system has avoided crosslinked caused above problem with within toxin parcel and the immunoliposome.We use the intravital transplanting ovarian cancer of anti-TFRscFv-lipo guiding Rhodopseudomonas exotoxin A (PE) treatment nude mice, and tumor is all disappeared, long-term disease free survival.Biotoxin commonly used comprises: Rhodopseudomonas extracellular toxin (PE)/Ricin (RA).
Claims (8)
1, a kind of tumour-specific targeting drug delivery system is characterized in that it comprises
One antibody is used for specific recognition and in conjunction with surface of tumor cells antigen;
One liposome is used for parcel and transportation treatment effector agent; And
One joint is used to connect described antibody and described liposome.
2, drug-supplying system according to claim 1 is characterized in that described antibody is monoclonal antibody.
3, drug-supplying system according to claim 2 is characterized in that described monoclonal antibody is anti-carcinoembryonic-antigen (CEA) antibody, anti-ferrum haemproteins antibody, anti-MAG antibody, anti-transferrin antibody.
4, drug-supplying system according to claim 3 is characterized in that described antibody is anti-transferrin antibody.
5, drug-supplying system according to claim 3 is characterized in that described antibody uses the variable region scFv of single-chain antibody.
6, drug-supplying system according to claim 1 is characterized in that described liposome is the liposome of cationic lipid.
7, drug-supplying system according to claim 1, described treatment effector agent is selected from: chemotherapeutics, radionuclide, immunotoxin, antioncogene, antisensenucleic acids at least a or several.
8, the application of tumour-specific targeting drug delivery system in preparation medicine for treating tumor thing.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009537526A (en) * | 2006-05-15 | 2009-10-29 | ジョージタウン・ユニバーシティ | Production and use of antibodies or antibody fragment targeted immunoliposomes for systemic administration of therapeutic or diagnostic agents |
| CN101120381B (en) * | 2005-02-14 | 2012-09-26 | 皇家飞利浦电子股份有限公司 | Apparatus and method for determining an injection point for targeted drug delivery |
-
2002
- 2002-04-04 CN CN 02105456 patent/CN1448183A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101120381B (en) * | 2005-02-14 | 2012-09-26 | 皇家飞利浦电子股份有限公司 | Apparatus and method for determining an injection point for targeted drug delivery |
| JP2009537526A (en) * | 2006-05-15 | 2009-10-29 | ジョージタウン・ユニバーシティ | Production and use of antibodies or antibody fragment targeted immunoliposomes for systemic administration of therapeutic or diagnostic agents |
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