CN1389472A - Immune conjugate of type-IV collagenase-resisting monoclonal antibody 3D6 and lidamycin for treating colorectal carcinoma and other digestive track tumors - Google Patents
Immune conjugate of type-IV collagenase-resisting monoclonal antibody 3D6 and lidamycin for treating colorectal carcinoma and other digestive track tumors Download PDFInfo
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Abstract
The invention refers to an anti-IV-type collagenous enzyme mono-antibody 3D6 which uses 2-imido-tetra-hydrogen thiophene (2-IT), N-hydroxyl-succimidic-meta-(N-Maleic imidic) benzoic acid ester (MBS) or other molecules of the cross-linking agents as the medium to be coupled up with the LiDa mycin (LDM), so as to gain the coupled substance of mono-antibody 3D6-LDM. The mono-antibody 3D6 is used to perform the chemical coloration of immune tissue on the enteron tumors of human colonic cancer, esophagus cancer, gastric cancer and so on, and the result shows that the expression and activation of the IV-type collagenous enzyme in said mentioned enteron tumor increase. The indirect ELISA method is used to determine the activity of the immune combination of the mono-antibody 3D6 with rat colonic cancer 26(C26), human colonic cancer HT-29.
Description
Technical field:
The present invention relates to a kind of immune conjugate formed by monoclonal antibody and antitumor drug and preparation method thereof and the application in neoplasm targeted therapy.
Background technology:
Monoclonal antibody (monoclonal antibody) 3D6 is with after the IV Collagen Type VI enzyme immunity BALB/c mouse, gets its splenocyte and mouse myeloma SP2/O cytogamy, the hybridoma cell strain excretory antibody that is obtained behind colony screening.This antibody molecule amount is about 150kDa, and its activity can combine and neutralize with IV Collagen Type VI enzyme spcificity.
It is reported, the growth of matrix metalloproteinase (MMPs) and malignant tumour, transfer and neovascularity exist confidential relation between generating, malignant tumour or its mesenchymal cell be by secreting multiple matrix metalloproteinase degrade basilar membrane and extracellular matrix components, thereby help the invasion and attack and the transfer process of tumour.Therefore, MMPs become noticeable oncotherapy molecular target (Drugs Aging 1997,11:229).IV Collagen Type VI enzyme, be called gelatinase again, comprise two components of MMP-2 and MMP-9, be the important member in the MMPs family, it can be degraded and make up the IV Collagen Type VI of support in the basilar membrane as other component, thereby help tumor cell destruction and penetrate basilar membrane attack and shift (Mol Med Today 2000,6:149).Studies show that in a large number, suppress the secretion of IV Collagen Type VI enzyme or other MMPs and active small-molecule drug thereof have in vivo the effect that suppresses tumor growth and transfer (J Natl Cancer Inst 2001,93:178).Because IV Collagen Type VI enzyme significantly increases in the expression and the activation of malignant tumor tissue, this laboratory is carried the monoclonal antibody targeted therapy that antitumor drug carries out with the Fab ' fragment of type-IV collagenase-resisting monoclonal antibody 3D6 in the past and has been obtained good effect, and has applied for patent (patent publication No. CN1268377A).This laboratory is found in the process that colorectal carcinoma and other digestive tract tumor tissue of people are studied, 3D6 carries out immunohistochemical staining with the type-IV collagenase-resisting monoclonal antibody, and digestive tract tumor tissue staining results such as people's colorectal carcinoma, the esophageal carcinoma and cancer of the stomach are positive.Wherein, when being dyeed, 5 routine human colon carcinoma tissues and normal adjacent tissue thereof find, the immunohistochemical staining of healthy tissues and monoclonal antibody 3D6 is negative, and colon cancer tissue then presents positive staining in various degree, shows that IV Collagen Type VI enzyme is specific expressed in tumor tissues.And the research of the digestive tract tumor of forming with monoclonal antibody 3D6 and Fab ' fragment thereof and antitumor drug such as immune conjugate treatment colorectal carcinoma does not appear in the newspapers as yet.Lidamycin as antineoplastic antibiotic (LDM) (the Chinese microbiotic magazine of developing voluntarily with this institute 1994,19 (2): 164) as the bullet medicine, the present invention has prepared monoclonal antibody 3D6-LDM conjugate, and has observed its anti-tumor in vivo effect to mouse transplantability colorectal carcinoma C26.The result shows that compare with the free lidamycin (LDM) of Isodose, the antitumor action of 3D6-LDM conjugate significantly strengthens.Therefore, the 3D6-LDM conjugate might become the new type antineoplastic medicine of digestive tract tumor such as treatment colorectal carcinoma.
The objective of the invention is to prepare the conjugate of monoclonal antibody 3D6-LDM, and this conjugate is used for the treatment of digestive tract tumor such as colorectal carcinoma with suitable method.
Summary of the invention:
1. monoclonal antibody 3D6-LDM conjugate monoclonal antibody 3D6-LDM conjugate involved in the present invention is type-IV collagenase-resisting monoclonal antibody 3D6 and antitumor antibiotics LDM with 1: 1 molecular ratio, connects formed chemo-immunity conjugate by micromolecular linking agent.A kind of molecular structure wherein by link molecule 2-imino-tetramethylene sulfide (2-IT) and N-hydroxy-succinamide base--(N-dimaleoyl imino) benzoic ether (MBS) etc. is connected to form (Figure 1A); The another kind of molecular structure of 3D6-LDM involved in the present invention can be for connecting formed chemo-immunity conjugate (Figure 1B) by link molecule such as N-hydroxy-succinamide base-3-(2-pyridine disulfide group)-propionic ester (SPDP) etc.The 3D6-LDM conjugate through the sodium dodecyl sulfate-polyacrylamide gel electrophoresis determining molecular weight about 160kDa.Wherein the molecular weight of monoclonal antibody 3D6 is about 150kDa, and the molecular weight of LDM is 11349Da, and the molecular weight of conjugate is equivalent to both sums, illustrates that the molecular ratio of monoclonal antibody 3D6 and LDM is 1: 1 in the conjugate.
2. utilize type-IV collagenase-resisting monoclonal antibody 3D6 as the oriented carrier that carries antitumor drug with 2-IT and MBS as the preparation of the monoclonal antibody 3D6-LDM conjugate of corsslinking molecular: (1) monoclonal antibody 3D6 behind the hydroxyapatite column purification puts in the dialysis tubing that molecular weight cut-off is 10kDa the 0.05M borate buffer with pH8.0 and dialyses, and regulating its concentration is 5mg/ml.Get and be dissolved in the borate buffer that pH is 8.0 0.05M, concentration is that the 2-IT solution 10 μ l of 4 mg/ml add in the 3D6 solution of above-mentioned 5mg/ml, under the condition of inflated with nitrogen in room temperature reaction 40min.After reaction finished, putting molecular weight cut-off was in the centrifugal evaporating pipe of 30kDa, and with 0.05M, pH is that 6.8 phosphate buffered saline buffer (PB) carries out buffer-exchanged, and centrifugally removed unreacted 2-IT.(2) power taking reaches the concentration that is made into 5mg/ml among the PB that mycin is dissolved in 0.05M pH6.8, stirs that to add the concentration that is dissolved in DMF down be the MBS of 10mg/ml, room temperature reaction 40min.After reaction finishes, put in the dialysis tubing that molecular weight cut-off is 10kDa, with 0.05M, the PB of the pH6.8 16h that fully dialyses.After finishing, dialysis carries out linked reaction with the monoclonal antibody 3D6 that modifies through 2-IT immediately, room temperature reaction 6h or spend the night.Reaction solution is put in the centrifugal evaporating pipe of ultrafiltration that molecular weight cut-off is 30kDa, and centrifugal ultrafiltration 3-4 time is removed the lidamycin (LDM) that unreacted MBS modifies, and obtains the conjugate of 3D6-LDM.
3. with the preparation as the 3D6-LDM conjugate of corsslinking molecular of N-hydroxy-succinamide base-3-(2-pyridine the disulfide group)-propionic ester (LC-SPDP) of SPDP or long-chain: get in the phosphate buffered saline buffer (PBS) that LDM 2mg is dissolved in pH7.4 (1), be made into the concentration of 4mg/ml, adding mole number then is 10 times of excessive SPDP or LC-SPDP (15mg/ml, be dissolved in the dimethyl formamide), room temperature reaction 30min.React fully dialysis in the acetate buffer solution (pH4.5) that the rearmounted concentration of end is 0.1mol/L.Getting dialyzed solution adding DTT (DTT) is 10mmol/L to final concentration, and room temperature reaction 30min puts fully dialysis in the phosphate buffered saline buffer then.(2) getting monoclonal antibody 3D6 2mg in addition, to be dissolved in pH be 6.8, and concentration is in the phosphate buffered saline buffer of 0.2mol/L, and adding mole number is 10 times of excessive SPDP or LC-SPDP, room temperature reaction 30min, fully dialysis in PBS liquid.(3) dialyzed solution in the merging (1) and (2), room temperature reaction spends the night.Separate through Sephadex G-75 post then, collect first peak, obtain the conjugate of 3D6-LDM.
The immunoreactivity of the present invention's said monoclonal antibody 3D6-LDM conjugate and IV Collagen Type VI enzyme and tumour cell experiment showed, that this conjugate has kept the binding ability with IV Collagen Type VI enzyme and above-mentioned various tumour cells.The said monoclonal antibody 3D6 of the present invention shows in the immunohistochemical staining experimental result of different people tumor tissues, digestive tract tumor tissues such as colorectal carcinoma monoclonal antibody 3D6 is presented positive staining and in the healthy tissues around the colorectal carcinoma dyeing negative, illustrate that the expression of IV Collagen Type VI enzyme in colon cancer tissue has specificity.The said 3D6-LDM conjugate of the present invention shows that to the lethal effect experiment of tumour cell the 3D6-LDM conjugate is stronger to the cytotoxicity of tumour cell than using LDM separately, and becomes dependence with the concentration of conjugate.And during the said 3D6-LDM conjugate of the present invention intravenous administration, to the result of treatment of mouse junction cancer apparently higher than independent use LDM.
The embodiment of following the anti-tumor activity for the 3D6-LDM conjugate, just illustrative for the purpose of the present invention, and nonrestrictive.
Embodiment 1:
The immunoreactivity of monoclonal antibody 3D6 and 3D6-LDM conjugate and IV Collagen Type VI enzyme and tumour cell is carried out with the ELISA method.Monoclonal antibody 3D6 presents good immunity with human colon carcinoma HT-29 cell, mouse junction cancer C26 cell, human oral squama cancer KB cell, rat liver cancer H22 cell and combines active (Fig. 2).Measure the immune binding ability of monoclonal antibody 3D6-LDM conjugate and IV Collagen Type VI enzyme and human colon carcinoma HT-29 cell, mouse junction cancer C26 cell, human oral squama cancer KB cell, rat liver cancer H22 cell after the coupling, the result shows that the 3D6-LDM conjugate has kept the binding ability (Fig. 4) of monoclonal antibody 3D6 and IV Collagen Type VI enzyme (Fig. 3) and above-mentioned various tumour cells.
Embodiment 2:
Monoclonal antibody 3D6 when digestive tract tumor tissues such as many cases people colorectal cancer, carcinoma of cecum, the esophageal carcinoma, cancer of the stomach are carried out immunohistochemical staining, presents high positive reactivity (table 1) at the immunohistochemical staining monoclonal antibody 3D6 of different people tumor tissues.Tissue slice in the experiment is equipped with blank (substituting monoclonal antibody 3D6 with PBS), negative control (reach mycin monoclonal antibody F9 with irrelevant drag and substitute monoclonal antibody 3D6), coloration result is all negative, and the immunohistochemical staining that proves monoclonal antibody 3D6 is the specific stain result at IV Collagen Type VI enzyme in the tissue.Immunohistochemical staining is the result show, monoclonal antibody 3D6 all has positive staining in various degree in digestive tract tumor tissues such as human body colorectal cancer, carcinoma of cecum, the esophageal carcinoma, cancer of the stomach.In the digestive tract tumor tissue samples, the dyeing multidigit of monoclonal antibody 3D6 is gone in the tumour cell of matrix or blood vessel in glandular cell sample tumour cell top and substrate and invasion and attack, and be strong positive dyeing, positive rate reaches 80% (32/40), shows that IV Collagen Type VI enzyme is in tumor cell destruction with penetrate in the process of basilar membrane and work.
Immunohistochemical staining tumor sample negative staining example number positive staining example number stained positive rate (%) colon cancer 1 21 95.2 carcinomas of cecum 13 75.0 cancer of the esophagus 23 60.0 cancer of the stomach 45 55.6 of table 1 monoclonal antibody 3D6 in the different people tumor tissues
In addition, observe the immunohistochemical staining of 5 routine colorectal carcinomas and normal adjacent tissue thereof, dyeing is negative in the healthy tissues, and the positive staining (table 2) of colon cancer tissue showed different, brown engrain particle is positioned at the top of glandular epithelium sample tumour cell in the tumour cell, between around indivedual cases see in the matter (Fig. 5, Fig. 6).The result has shown the specificity that IV Collagen Type VI enzyme is expressed in colon cancer tissue.
Table 2 semi-quantitative analysis monoclonal antibody 3D6 is in the immunohistochemical staining colon cancer case sequence number colon cancer tissue dyeing situation normal adjacent tissue dyeing situation 1 of colon cancer and normal adjacent tissue thereof ++ ++-2 +++-3+-4 ++ ++-
5 ++-
Embodiment 3:
The 3D6-LDM conjugate is measured the 3D6-LDM conjugate to the lethal effect of tumour cell with tetrazole indigo plant (MTT) method and is reached free lidamycin (LDM) to the colorectal carcinoma C26 cell of vitro culture and the lethal effect of liver cancer H22 cell, and the free lidamycin (LDM) of result is respectively 4.8 * 10 to the IC50 of two kinds of cells
-11Mol/L and 6.2 * 10
-11Mol/L, 3D6-LDM conjugate show the stronger vitro cytotoxicity of specific ionization lidamycin (LDM), and the IC50 of two kinds of cells is respectively 4.3 * 10
-12Mol/L and 5.1 * 10
-12Mol/L.Lidamycin (LDM) and 3D6-LDM conjugate concentration dependent ground suppress the propagation (Fig. 7, table 4) of H22 cell.
Table 3 mtt assay mensuration lidamycin (LDM) and 3D6-LDM are at external lethal effect to liver cancer H22 cell
A560 (% contrast) drug level (mol/L * 10
-12)
LDM 3D6-LDM1000 27.73 18.63100 53.44 26.2910 74.80 60.041 78.40 64.180.1 80.41 78.670.01 82.41 83.02
Embodiment 4:
The mouse junction cancer C26 knurl piece of interior generation is got in the intravenous injection of 3D6-LDM conjugate to the curative effect of mouse junction cancer C26, after the homogenate with physiological saline by 1: 3 dilution proportion, it is subcutaneous only to be inoculated in the BALB/c mouse armpit by 0.2ml/ then, inoculate 72 hours posterior vein drug administration by injection, control group gives physiological saline, be administered once altogether, test the gross tumor volume of measuring each treated animal on the 10th day, and with knurl volume calculation tumour inhibiting rate.The result shows, 3D6-LDM conjugate 0.025mg/kg, and the tumour inhibiting rate of 0.05mg/kg and 0.10mg/kg dosage is respectively 54.5%, 70.3% and 81.2%, and the tumour inhibiting rate of 0.05mg/kg lidamycin (LDM) is 56.4%, significantly is lower than isodose conjugate (table 4).
Table 4 3D6-LDM intravenous administration is transplanted the growth-inhibiting effect of colorectal carcinoma C26 to mouse
Heavy (mg) drug dose (mg/kg) tumour inhibiting rate (%) of number of animals body weight (g) knurl
Beginning/finish beginning/end Xaver ± SD to contrast 10/10 18.4/18.2,1.01 ± 0.193D6,0.75 10/10 18.0/17.9,0.75 ± 0.20 25.7LDM, 0.05 10/10 18.1/18.3,0.44 ± 0.16 56.4*3D6+LDM 0.75+0.05,10/10 18.5/18.1,0.62 ± 0.13 38.6*3D6-LDM, 0.025 10/10 18.2/17.9,0.46 ± 0.09 54.5*3D6-LDM, 0.05 10/10 18.1/16.4,0.30 ± 0.06 70.3**3D6-LDM, 0.10 10/10 18.6/16.3,0.20 ± 0.06 81.2**
The subcutaneous vaccination tumour, the 3rd day intravenous administration is once;
* compare with control group P＜0.01, and compare with the lidamycin (LDM) group * * P＜0.01
The invention effect:
Advantage of the present invention and good effect are to be to have determined type-IV collagenase-resisting monoclonal antibody 3D6 and lidamycin The preparation method of conjugate observes the immunohistochemistry between the tumor in digestive tract such as monoclonal antibody 3D6 and colon cancer Reaction, the treatment that is used for the tumor in digestive tract such as colon cancer for monoclonal antibody 3D6-LDM conjugate provides experimental basis. Lidamycin is having the strongest CDCC and obvious anti-tumor in vivo effect being arranged of a kind of up to now report Antitumor antibiotics, just be in the research and development stage as a kind new medicine at present. Monoclonal antibody 3D6-LDM conjugate In the treatment to mouse bearing liver cancer, demonstrate good curative effect, and swollen to alimentary canals such as colon cancers about it The treatment of knurl does not still have report. Immunohistochemical staining experiment showed, that monoclonal antibody 3D6 is swollen at alimentary canals such as colon cancers Present positive reaction in the tumor tissue, and around in the normal structure dyeing negative. Enzyme-linked immunosorbent assay also Show, exist stronger between 3D6-LDM conjugate and mouse junction cancer C26 and the human colon carcinoma HT-29 cell Immunity in conjunction with activity. C26 shows specific ionization power with 3D6-LDM conjugate treatment mouse transplantability colon cancer Reach the stronger antitumor action of mycin. Therefore, the conjugate of expection monoclonal antibody 3D6 and lidamycin might be opened Sending out becomes novel antineoplastic guide medicine for clinical cancer therapy, and obtains good effect.
Description of drawings: the structural representation of Fig. 1 monoclonal antibody 3D6-LDM
Wherein A represents to be connected the 3D6-LDM that obtains with 2-IT as linking agent with MBS
B represents that with SPDP or LC-SPDP be the immunoreactivity that linking agent connects 3D6-LDM Fig. 2 monoclonal antibody 3D6 of obtaining and C26, HT-29, H22, KB cell
Wherein X-coordinate is antibody 3D6 concentration (μ g/ml)
Ordinate zou is the immunoreactivity of light absorption value Fig. 3 monoclonal antibody 3D6-LDM conjugate and monoclonal antibody 3D6 and the IV Collagen Type VI enzyme of 490nm
Wherein X-coordinate is antibody concentration (μ g/ml)
Ordinate zou is the immunoreactivity of 490nm light absorption value Fig. 4 monoclonal antibody 3D6-LDM conjugate to C26, HT-29, H22, KB cell
Wherein X-coordinate is 3D6-LDM concentration (μ g/ml)
Ordinate zou is the result of 490nm light absorption value Fig. 5 monoclonal antibody 3D6 and the histochemical stain of human colon carcinoma histogenic immunity
Show among the figure and amplify 400 times colon cancer tissue, the normal colon in left side does not have positive staining, and the right side is knot
The intestinal cancer tissue, positive particle is distributed in cell top, scale length in the visible glandular cell sample tumour cell
Be 100 μ m.The result of a Fig. 6 monoclonal antibody 3D6 and a routine human colon carcinoma histogenic immunity histochemical stain
Show the colon cancer tissue of 100 times of 1 example amplifications among the figure, the upper left side is normal colon, and dyeing is negative,
Bottom-right tumor tissues is strong positive dyeing, and the brown particle of engrain is positioned at the endochylema of tumour cell,
Scale length is 400 μ m.Fig. 7 lidamycin (LDM) and monoclonal antibody 3D6-LDM conjugate are to the restraining effect (mtt assay) of H22 cell proliferation
Wherein X-coordinate is the logarithm of the concentration of lidamycin (LDM) and 3D6-LDM, i.e. log (mol/L)
Ordinate zou is cell survival rate (%), and T/C is dosing group survivaling cell number/not dosing group cell survivaling number.
Claims (3)
1. the immune conjugate of type-IV collagenase-resisting monoclonal antibody 3D6 and lidamycin (LDM) (LDM), it is characterized in that monoclonal antibody 3D6-LDM conjugate is the immune conjugate that is 1: 1 by monoclonal antibody 3D6 that forms as joint by micromolecular linking agent between the amino on amino on the monoclonal antibody 3D6 protein molecular and the LDM apoprotein molecule and LDM molecular ratio, the molecular weight of conjugate is about 160kDa, the small molecules joint that wherein is used to connect monoclonal antibody 3D6 and LDM can be 2-imido grpup tetramethylene sulfide (2-IT) and N-hydroxy-succinamide base--(N-dimaleoyl imino) benzoic ether (MBS), also can be that N-hydroxy-succinamide base-3-(2-pyridine disulfide group)-propionic ester (SPDP) waits the special-shaped bi-functional cross-linking agent of other small molecules.
2. the preparation method of the immune conjugate of type-IV collagenase-resisting monoclonal antibody 3D6 and lidamycin (LDM) (LDM), the preparation that it is characterized in that said conjugate be with lidamycin (LDM) earlier with special-shaped bi-functional cross-linking agent such as N-hydroxy-succinamide base--(N-dimaleoyl imino) benzoic ether (MBS) modifies, add monoclonal antibody 3D6 then, the purified product that obtains in reaction back through 2-imido grpup tetramethylene sulfide (2-IT) sulfhydrylation; Or lidamycin (LDM) carried out linked reaction with N-hydroxy-succinamide base-3-(2-pyridine the disulfide group)-propionic ester special-shaped bi-functional cross-linking agents such as (LC-SPDP) of other special-shaped bi-functional cross-linking agent such as N-hydroxy-succinamide base-3-(2-pyridine disulfide group)-propionic ester (SPDP) or long-chain as mesosome and monoclonal antibody 3D6, the purified product that obtains in reaction back.
3. the application of type-IV collagenase-resisting monoclonal antibody 3D6 and lidamycin (LDM) (LDM) conjugate in digestive tract tumor such as treatment colorectal carcinoma.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101314619B (en) * | 2007-06-01 | 2010-12-22 | 齐鲁制药有限公司 | Tumour treatment vaccine CTP37CRM197 immunogen, preparation method and application thereof |
| CN101437852B (en) * | 2006-03-17 | 2013-06-12 | 健泰科生物技术公司 | Anti-TAT226 antibodies and immunoconjugates |
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2002
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101437852B (en) * | 2006-03-17 | 2013-06-12 | 健泰科生物技术公司 | Anti-TAT226 antibodies and immunoconjugates |
| CN101314619B (en) * | 2007-06-01 | 2010-12-22 | 齐鲁制药有限公司 | Tumour treatment vaccine CTP37CRM197 immunogen, preparation method and application thereof |
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