IE58638B1 - A tumor therapeutic agent and a process for its preparation - Google Patents
A tumor therapeutic agent and a process for its preparationInfo
- Publication number
- IE58638B1 IE58638B1 IE219185A IE219185A IE58638B1 IE 58638 B1 IE58638 B1 IE 58638B1 IE 219185 A IE219185 A IE 219185A IE 219185 A IE219185 A IE 219185A IE 58638 B1 IE58638 B1 IE 58638B1
- Authority
- IE
- Ireland
- Prior art keywords
- therapeutic agent
- treatment
- cells
- preparation
- nca
- Prior art date
Links
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- 235000012538 ammonium bicarbonate Nutrition 0.000 description 2
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- 125000000524 functional group Chemical group 0.000 description 1
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- 238000000265 homogenisation Methods 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
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- 238000011081 inoculation Methods 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
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- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
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- 239000002504 physiological saline solution Substances 0.000 description 1
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- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Oncology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
- Measuring Pulse, Heart Rate, Blood Pressure Or Blood Flow (AREA)
- Window Of Vehicle (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
The process entails either tumour cells which carry antigens which are bound by the monoclonal antibodies described in German Offenlegungsschrift 33 29 184 being dried or stabilised by a chemical treatment, or antigens being isolated from human cells using these monoclonal antibodies, and converted into a therapeutic agent, adding neuraminidase where appropriate.
Description
The invention relates to a process for the preparation of a therapeutic agent from tumor cells for the therapy of tumorous diseases, and to a therapeutic agent of this type.
It is known, for example from Mechanisms of Tumor Immunity," Gree et al., eds., John Wiley and Sons, N.Y., 1977, page 196, that attempts have already been made to treat tumorous diseases by inoculation with tumor cells which have been modified by freezing and thawing, freezedrying, pressure or homogenization. Subcellular fractions or cell extracts have also been used for this purpose. However, as yet no vaccine against a tumorous disease has been disclosed.
We have found, surprisingly, that cells, which have been freeze-dried or treated with an aldehyde, from human tumors or from cell aggregates obtained from the latter, which carry the antigens CEA or NCA can be used as a therapeutic agent for the treatment of tumorous diseases.
Thus the invention relates to a therapeutic agent for the treatment of a tumorous disease, containing human tumor cells which have been freeze-dried or stabilized by a chemical treatment and which carry the membrane-associated antigens CEA or NCA.
One advantage of a therapeutic agent of this type compared with the use. of unmodified celts is that unmodified cells are not stable, so that they have to be prepared fresh each time. Moreoever, for this reason, they cannot be standardized.
The invention furthermore relates to a process for the preparation of a therapeutic agent for the treatment of a tumorous disease, which comprises the freeze-drying or stabilization, by a chemical treatment, and the processing to a therapeutic agent, neuraminidase being added where appropriate, of human tumor cells which carry the antigens CEA or NCA.
The possibility of potentiating an immune response by neuraminidase is disclosed in German OffenIegungsschrift 2,620,649.
A therapeutic agent is to be understood to be an 5 agent which may be suitable both as a prophylatic and for the treatment of a manifest disease.
The cells which can be used within the scope of the invention are obtained from tumors by known cell culture processes. Cells which have been obtained from such cul10 tures by mechanical or enzymatic means and have, where appropriate, been inactivated with mitomycin C, are dried, preferably freeze-dried, or treated with an agent known to those skilled in the art as a stabilizing agent for organic tissue, preferably a raonoaIdehyde or dialdehyde having 1 to 6 carbon atoms.
The agents which are particularly suitable for chemical stabilization and fixation include, in particular, bifunctional compounds, that is to say those which contain two groups which can react with functional groups on the biological material - in other words can crosslink*’ it. Examples of these are dialdehydes, in particular aliphatic dialdehydes having 2-8 carbon atoms. However, monoalkanals having 1-4 carbon atoms, such as formaldehyde, which can undergo bifunctional reactions, as well as bi25 functional imino esters, such as suberimi date, isocyanates or isothiocyanates, are also suitable for this purpose.
It is also possible for so-called tanning agents such as, for example, tannic acid and its derivatives, or chromium salts, to be used as agents which can stabilize biological material. SulfosaIicyIic acid is also suitable.
In general, the cells are in the form of cell aggregates or single cells.
Examples of antigens are CEA (carcinoembyronic antigen; J.exp. Red. <1965) 122, *67) NCA (nonspecific crossreacting antigen; J. Immun. (1973) III, 1926) which can be isolated from the tumor cells by immunoadsorption chromatography. For this purpose, the monoclonal antibodies described in Table I of German Offenlegungsschrift 3,416,774 are covalently bound as purified proteins, to CN8r-activated sepharose 4B, and the antigens (CEA, NCA) recognised by these monoclonal antibodies, are isolated from DE-TA colon carcinoma cell extracts. A suitable process is described in the Pharmacia book Affinity Chromatography, Principles and Methods, 12-18 (1979), summarized on page 15.
Quality control of a material which is to be used as a vaccine is carried out by, for pxample, typing with monoclonal antibodies, or by fractionation of the total cellular proteins using SDS-polyacrylamide gel electrophoresis or isoelectric focusing (1st dimension) combined with SDS-polyacrylamide gel electrophoresis (2nd dimension) followed by staining of the gel (silver stain).
The antigenic material is preferably administered intradermally, preferably by the checkerboard vaccination method (Cancer Immunol, and Immunother. 6,47-58 (1979), in particular page 48) in combination with an adjuvant, in particular neuraminidase (German Offenlegungsschrift 2,620,649).
A vaccine of this type is preferably used for certain stages of colon carcinoma (Duke C) and for other tumors which carry antigens or epitopes which are present in the vaccine. Other tumors of this type are solid tumors, for example carcinomas of the pancreas, of the stomach, of the breast and of the lungs. The vaccine can be administered parenterally or orally. The antigens can be administered dissolved or suspended in physiological saline, preferably intradermally in PBS.
Two tests were carried out to assess the stability of the antigenic composition of the vaccine: a) the Terasaki IIP Assay (indirect immunofluorescence using tumor cells which grow in the wells of the Terasaki microtiter plate) with monoclonal antibodies of various specificities. It is possible by means of this test to measure the expression of membrane antigens on intact tumor cells, against which a number of monoclonal antibodies are available (Cancer Detection and Prevention <5, 181-184, 1983). It was possible by this means to detect drastic changes to the DE-TA cell membrane during cultivation; b) solubilization of the total cellular proteins using a detergent (Hybridoma 1_, 413-421, 1982) followed by SDSpolyacrylamide gel electrophoresis combined with a silver stain (Anal. Biochem. 105, 361-363,1980). The combination of these techniques ensures that no significant changes in the total protein content of the DE-TA cell line have occurred.
The examples which follow illustrate the invention. Example 1 The carcinoma cell line BW X was cultivated in a cell culture in plastic bottles, growing as a monolayer in RPMI-1640 medium (Moore, G.E., Gerner, R.E., Franklin, H.A., Culture of normal human leukocytes, J.A.M.A. 199, 519-524 (1967)) with 10X fetal calf serum. The adherent cells growing in confluent cultures were separated mechanically or using trypsin which was dissolved in RPMI-1640 medium containing no fetal calf serum, the collagenase was inactivated by addition of fetal calf serum dissolved in RPMI-1640, and then the cells were detached from the tissue culture bottles and washed 3 times in phosphate-buffered saline (PBS) at 37°C.
About 107 cells, the major part of which as in the form of aggregates, were incubated at 37°C for 1 hour in T ml of PBS which contained 100 pg of mitomycin C.
Then the cells thus inactivated were washed 3 times with PBS and a) washed 3 times in 0.18 molar ammonium bicarbonate buffer which had been adjusted to pH 7.4 with acetic acid. A cell sediment corresponding to 107 cells was taken up in 100 pi of the same ammonium bicarbonate buffer and frozen at -70°C. The frozen material was then freeze-dried and stored in a small glass bottle, which was closed aii—tight, in a refrigerator at +4°C. The cell material thus treated can, after having been taken up in PBS, be used for vaccination of patients.
Alternatively b) incubated with 0.1% glutaraldehyde in PBS at +4°C for minutes, the excess glutaraldehyde being removed by washing 3 times with PBS, and then incubated with 2X BSA (Bovine Serum Albumin) at +4°C for 5 minutes and washed 3 times in PBS. The cells thus treated can be stored at ♦4°C and used for the vaccination of patients.
Or c) incubated in formalin according to Lilly (Benno Romeis (1968), page 65, section 266, Oldenburg Verlag, Munich) at 25°C overnight, shaking occasiona11y. The cells (about 108) were centrifuged with decantation of the supernatant (10 minutes at 800 x g), and the cell sediment was suspended in 7 ml of double-distilled water (= 1st wash). This washing process was repeated 4 times at intervals of 1 hour. The cell sediment was then washed 3 times, at intervals of 1 hour, in 7 ml of 70X ethanol each time. The cell sediment was then washed 3 times, at intervals of 30 minutes, in 7 ml of 80X ethanol each time. The cell sediment was then washed 3 times, at intervals of 30 minutes, in 7 ml of 96X ethanol each time. The cell sediment was then washed 3 times, at intervals of 30 minutes, in 7 ml - 7 of 99% ethanol each time. The cell sediment was then washed 3 times, at intervals of 30 minutes, in 7 mt of sterile PBS each time, and was stored sterile at 4°C.
The cells thus treated can be stored at 4°C and used for the vaccination of patients.
Claims (6)
1. A therapeutic agent for the treatment of a tumorous disease, containing human tumor cells which have been freeze-dried or stabilized by a chemical 5 treatment and which carry the membrane-associated antigens CEA or NCA.
2. A therapeutic agent as claimed in claim 1, which contains an adjuvant which potentiates the immune response, preferably neuraminidase. 10
3. A process for the preparation of a therapeutic agent for the treatment of a tumorous disease, which comprises the freeze-drying or stabilization by a chemical treatment, and, the processing to a therapeutic agent, of human tumor cells which carry the membrane15 associated antigens CEA or NCA.
4. The process as claimed in claim 3, wherein an adjuvant which potentiates the immune response, preferably neuraminidase, is additionally added to the therapeutic agent. 20
5. The use of human tumor cells which carry the membrane-associated antigens CEA or NCA, where appropriate in combination with an adjuvant which potentiates the immune response, preferably neuraminidase, for the preparation of a therapeutic 25 agent for the treatment of tumorous diseases.
6. A therapeutic agent as claimed in claim 1, substantially as hereinbefore described and exemplified.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843432714 DE3432714A1 (en) | 1984-09-06 | 1984-09-06 | TUMOR THERAPEUTICS AND METHOD FOR THE PRODUCTION THEREOF |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE852191L IE852191L (en) | 1986-03-06 |
| IE58638B1 true IE58638B1 (en) | 1993-10-20 |
Family
ID=6244749
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE219185A IE58638B1 (en) | 1984-09-06 | 1985-09-05 | A tumor therapeutic agent and a process for its preparation |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0173951B1 (en) |
| JP (1) | JPS6168427A (en) |
| AT (1) | ATE64531T1 (en) |
| CA (1) | CA1277600C (en) |
| DE (2) | DE3432714A1 (en) |
| DK (1) | DK172253B1 (en) |
| ES (1) | ES8704082A1 (en) |
| FI (1) | FI88360C (en) |
| GR (1) | GR852149B (en) |
| IE (1) | IE58638B1 (en) |
| IL (1) | IL76289A (en) |
| PT (1) | PT81093B (en) |
| ZA (1) | ZA856807B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3806565A1 (en) * | 1988-03-01 | 1989-09-14 | Deutsches Krebsforsch | VIRUS-MODIFIED TUMOR VACCINES FOR THE IMMUNOTHERAPY OF TUMOR METAL KEYS |
| AT398900B (en) * | 1991-02-12 | 1995-02-27 | Pekar Rudolf Dr | Vaccine for immunotherapy |
| US7105159B1 (en) | 1992-11-05 | 2006-09-12 | Sloan-Kettering Institute For Cancer Research | Antibodies to prostate-specific membrane antigen |
| US7070782B1 (en) | 1992-11-05 | 2006-07-04 | Sloan-Kettering Institute For Cancer Research | Prostate-specific membrane antigen |
| US6953668B1 (en) | 1992-11-05 | 2005-10-11 | Sloan-Kettering Institute For Cancer Research | Prostate-specific membrane antigen |
| ATE342356T1 (en) * | 1992-11-05 | 2006-11-15 | Sloan Kettering Inst Cancer | PROSTATE-SPECIFIC MEMBRANE ANTIGEN |
| US6569432B1 (en) | 1995-02-24 | 2003-05-27 | Sloan-Kettering Institute For Cancer Research | Prostate-specific membrane antigen and uses thereof |
| CA2212846A1 (en) | 1995-02-24 | 1996-08-29 | Sloan-Kettering Institute For Cancer Research | Prostate-specific membrane antigen and uses thereof |
| DE19506483A1 (en) * | 1995-02-24 | 1996-08-29 | Jens Dr Dr Atzpodien | Antitumour vaccines |
| AU2002356844C1 (en) | 2001-10-23 | 2010-03-04 | Amgen Fremont Inc. | PSMA antibodies and protein multimers |
| US20050215472A1 (en) | 2001-10-23 | 2005-09-29 | Psma Development Company, Llc | PSMA formulations and uses thereof |
| CN1315536C (en) * | 2002-09-13 | 2007-05-16 | 李进 | Novel vaccine of tumor antigen, its preparation method and vaccine composition |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4152410A (en) * | 1975-09-03 | 1979-05-01 | Eisai Co., Ltd. | Diagnosis reagent for neoplasm and method for diagnosis of neoplasm |
| DE2643215A1 (en) * | 1976-09-25 | 1978-04-06 | Bayer Ag | CANCEROSTATICALLY EFFECTIVE PREPARATIONS FROM TUMOR CELLS AND A METHOD FOR THEIR PRODUCTION |
| ZA776822B (en) * | 1976-11-24 | 1979-06-27 | D Mccollester | Vaccine and method for immunotherapy of neoplastic disease |
| DE2918927A1 (en) * | 1979-05-10 | 1980-11-20 | Hans Prof Dr Limburg | MEDICINAL PRODUCT FOR TREATING CARCINOMAS AND METHOD FOR THE PRODUCTION THEREOF |
| US4446122A (en) * | 1979-12-28 | 1984-05-01 | Research Corporation | Purified human prostate antigen |
| US4468457A (en) * | 1981-06-01 | 1984-08-28 | David M. Goldenberg | Method for producing a CSAp tryptic peptide and anti-CSAp antibodies |
| DE3329184A1 (en) * | 1983-08-12 | 1985-02-21 | Behringwerke Ag, 3550 Marburg | MONOCLONAL ANTIBODIES WITH SPECIFICITY FOR MEMBRANE-ASSOCIATED ANTIGENS |
| DE3416774A1 (en) * | 1984-05-07 | 1985-11-14 | Behringwerke Ag, 3550 Marburg | MONOCLONAL ANTIBODIES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
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1984
- 1984-09-06 DE DE19843432714 patent/DE3432714A1/en not_active Withdrawn
-
1985
- 1985-08-27 DE DE8585110757T patent/DE3583265D1/en not_active Expired - Fee Related
- 1985-08-27 AT AT85110757T patent/ATE64531T1/en not_active IP Right Cessation
- 1985-08-27 EP EP85110757A patent/EP0173951B1/en not_active Expired - Lifetime
- 1985-09-03 DK DK402485A patent/DK172253B1/en not_active IP Right Cessation
- 1985-09-04 GR GR852149A patent/GR852149B/el unknown
- 1985-09-04 FI FI853389A patent/FI88360C/en not_active IP Right Cessation
- 1985-09-04 ES ES546701A patent/ES8704082A1/en not_active Expired
- 1985-09-04 IL IL76289A patent/IL76289A/en not_active IP Right Cessation
- 1985-09-05 JP JP60195000A patent/JPS6168427A/en active Pending
- 1985-09-05 IE IE219185A patent/IE58638B1/en not_active IP Right Cessation
- 1985-09-05 PT PT81093A patent/PT81093B/en not_active IP Right Cessation
- 1985-09-05 ZA ZA856807A patent/ZA856807B/en unknown
- 1985-09-05 CA CA000490026A patent/CA1277600C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| FI88360B (en) | 1993-01-29 |
| DK402485A (en) | 1986-03-07 |
| PT81093B (en) | 1988-07-01 |
| IE852191L (en) | 1986-03-06 |
| ATE64531T1 (en) | 1991-07-15 |
| EP0173951A3 (en) | 1988-06-08 |
| JPS6168427A (en) | 1986-04-08 |
| CA1277600C (en) | 1990-12-11 |
| FI88360C (en) | 1993-05-10 |
| ES546701A0 (en) | 1987-03-16 |
| FI853389L (en) | 1986-03-07 |
| DK402485D0 (en) | 1985-09-03 |
| IL76289A0 (en) | 1986-01-31 |
| ZA856807B (en) | 1986-04-30 |
| PT81093A (en) | 1985-10-01 |
| FI853389A0 (en) | 1985-09-04 |
| DE3583265D1 (en) | 1991-07-25 |
| IL76289A (en) | 1992-01-15 |
| ES8704082A1 (en) | 1987-03-16 |
| EP0173951B1 (en) | 1991-06-19 |
| GR852149B (en) | 1986-01-03 |
| DK172253B1 (en) | 1998-02-09 |
| EP0173951A2 (en) | 1986-03-12 |
| DE3432714A1 (en) | 1986-04-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |