GB2147806A - Refined detoxified endotoxin compositions - Google Patents
Refined detoxified endotoxin compositions Download PDFInfo
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- GB2147806A GB2147806A GB08420612A GB8420612A GB2147806A GB 2147806 A GB2147806 A GB 2147806A GB 08420612 A GB08420612 A GB 08420612A GB 8420612 A GB8420612 A GB 8420612A GB 2147806 A GB2147806 A GB 2147806A
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- rde
- endotoxin
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- detoxified endotoxin
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/05—Immunological preparations stimulating the reticulo-endothelial system, e.g. against cancer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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- 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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55544—Bacterial toxins
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Abstract
A composition which is capable of producing an effective adjuvant response or stimulating the immune response of a warm blooded animal which comprises an effective amount of a refined detoxified endotoxin material, in combination with a pharmaceutically acceptable carrier.
Description
SPECIFICATION
Refined detoxified endotoxin
Background of the invention
The present invention is directed to the use of a refined detoxified endotoxin (RDE) product as a potent immunostimulator and also as an adjuvant. The RDE used in the present invention is characterized as having no detectable 2-keto-3-deoxyoctanoate, between about 350 and 475 nmoles/mg of phosphorus and between about 1700 and 2000 nmoles/mg of fatty acids.
Endotoxic extracts obtained from Enterobacteriaciae including parent organisms and mutants are known.
These extracts have been used for immunotherapy of various immunogenic tumors [see Peptides as
Requirement for Immunotherapy of the Guinea-Pig Line- 10 Tumorwith Endotoxins; Ribi, et al Cancer
Immunol. Immunother., Vo!. 7, pgs 43-58 (1979) incorporated herein by reference]. However, the endotoxin extracts are known to be highly toxic and, therefore, of limited use in the treatment of cancerous tumors.
Efforts have been made to "detoxify" the endotoxins while retaining its tumor regressive capacity. As shown, in Ribi, et al, supra, chemical procedures known to "detoxify" endotoxins while retaining adjuvanticity, such as succinylation and phthalylation resulted in both loss of endotoxicity and tumor regressive potency. Therefore, prior art attempts to obtain a refined detoxified endotoxin product have thus far not been successful.
Endotoxin extracts of the type used as a starting material to produce the RDE used in the present invention may be obtained from any Enterobacteriaciae including parent organisms and mutants. By way of example, the following genera are illustrative of the type of microorganisms that may be used:
Salmonella, Shigella, Escherichia, Bruce/la, Bordetella, Citrobacter, Pseudom on as, Pasturella, Neisseria,
Proteus, Klebsiella, and Serratia.
The following species are typically employed:
S.minnesota, S.typhimurium, B.pertussis, B.abortus, S. en teritidis, E.coli, S.typhi, S.marcescens, S.typhosa, Shigella flexni, and S.abortus equi.
The endotoxic extracts used as a starting material may be prepared by one of several known methods [see, for example, Webster, M.E., Sagin, J.F., Landy, M., and Johnson, A.G., J. Immunol. 1955, 744,55; Westphal,
O., Luderitz, 0., and Bister, F., Z. Naturforsch, 76148 (1952); Westphal, O., Pyrogens, Polysaccharides in
Biology, Tr. Second Macy Conference (George F. Springer, ed.), Madison, N.J. Madison Printing Co., 1957, 115; Galanos, C., Luderitz, O., Westphal, O., Eur. J. Biochem. 9, 245 (1969); Chen, C.H., Johnson, A.G., Kasai,
N., Key B.A., Levin, J., Nowotny, A., J. Infect. Dis. 128543 (1973); Ribi, E. Haskins, W.T., Landy, M., Miner,
K.C., The Journal of Experimental Medicine 114647(1961); Leive, L., Biochem. Biophys. Res.Comm. 21 290 (1965); and Ribi, E., Miner, K.C., and Perrine, T., J. Immunol. 8275(1959)].
A most suitable method of obtaining the endotoxic extract is that disclosed by Chen, et al., namely, methanol-chloroform precipitation.
The methanol-chloroform precipitate (MCP) is reacted with an organic or inorganic acid and then lyophilized to produce a hydrolyzed crude lipid A with reduced toxicity and pyrogenicity as compared with the starting endotoxin material. The resulting product is then treated with a solvent which is capable of specifically dissolving fatty acids and other impurities without dissolving the crude lipid A. A suitable solvent for this purpose is acetone. A phosphate content of the detoxified, refined lipid A is about one-half that observed for the toxic counterpart suggesting that the phosphate content is related to the toxic effects of endotoxins.
Suitable inorganic acids used to react with MCP are hydrochloric acid, sulfuric acid or phosphoric acid and the suitable organic acids are toluene sulfonic acid ortrichloroacetic acid. The reaction may be suitably conducted at a temperature between about 90" to 1 30"C. for a time sufficient to complete hydrolysis usually between about 15 and 60 minutes.
The preparation of crude detoxified endotoxin may also be accomplished by reacting the starting material with the selected acid in the presence of an organic solvent such as chloroform, methanol, and ethanol or combinations thereof.
The resulting crude lipid A is dissolved in acetone which is particularly suited to remove the fatty acid components. The solvent is then removed to produce crude detoxified endotoxin.
The crude detoxified endotoxin is then dissolved in a solvent and passed through a suitable chromatographic column such as, for example, a molecular exclusion chromatographic column, to separate the RDE fractions which are then combined after removed of the solvent. In one embodiment, the crude detoxified endotoxin solution is passed through a Sephadex column in the presence of a solvent such as chloroform, methanol, acetone, pyridine, ether or acetic acid or combinations thereof. The pressure of the column may vary but is typically in the range of between about atmospheric and 100 Ibs/in2 and the flow rate is between about Q,1 and 16 ml/mln,
Alternatively, the crude detoxified endotoxin solution is passed through a DEAE-cellulose column under the same pressure conditions as mentioned above for the Sephadex column.The flow rate may be maintained between about 2 and 15 ml/min. The solvents used are also the same as used for the Sephadex column although water and/or diethylamine can be added to all mixtures at a concentration of up to about 1%.
Other methods of producing RDE from crude detoxified endotoxin include passing the solution through a low pressure silica-gel 60 column having a particle size of between about 15 and 63 microns and using a suitable solvent such as chloroform, methanol, water or ammonium hydroxide. The preferred volume ratio of the aforementioned solvent mixture is about 50:25:4.2.
It is, therefore, an object of the present invention to employ a refined detoxified endotoxin product which can be effectively used to stimulate the immune system of a warm blooded animal. Specifically, RDE can be used as a B-cell mitogen, to stimulate the production lymphokines, stimulate macrophages, and as an adjuvant which enhances the immune response of a warm blooded animal.
Summary of the invention
The present invention is directed to the use of refined detoxified endotoxin (RDE) as a stimulant of the immune system. The RDE used in this invention has no detectable 2-keto-3-deoxyoctanoate, between about 350 and 475 nmoles/mg of phosphorus and between about 1700 and 2000 nmoles/mg of fatty acids.
The RDE of the present invention can be used as a stimulant of the immune response in warm blooded aminals against antigens such as microbacterial and fungal cells, microbacterial cell fragments, viruses, virus sub units synthetic peptides which mimic cellular and viral sub units. Specific antigens which are affected by the immune response augmented by the administration of RDE include cryptococcus neoformans candida spp., chlamydia spp., legionella spp. clostridia, hepatitis meningitis, streptococus spp, staphylococus spp., klebsiella spp., herpes virus, brucella spp., borditella spp., salmonella spp., shigelia spp., camphylobacter spp, yersinia spp., pasturella spp., francisella spp., listeria spp., and the like.
The RDE used in the present invention exhibits B-cell mitogenicity that is, RDE when administered to a warm blooded animal under a suitable dosage regimen activates B-lymphocytes which are the cells responsible for the manufacture of antibodies.
Assays (1) B Cell Mitogenicity - RDE is characterized by its ability to activate B lymphocytes which are the cells responsible for the manufacture of antibodies, as follows:
MITOGENIC ACTIVITY OF REFINED DETOXIFIED ENDOTOXIN
Dose 3H-thymidine incorporation (glmli CPM* BALBIc nu/+ 10 34,500 5.0 BALBIc nu/nu 10 38,693 5.6
Protocol 1 xl 06 cells/mI of each strain cultured with or without mitogens in 0.2 mg of RPMI-1640 (5% FCS) in 96 well
microtiter plates. 1 ucl 3H-Thymidine was added to each well the last 18 hours of a 48-hour incubation and
H-incorporation was measured by standard scintillation techniques
*CPM - counts per minute **SI-stimulation index
(2) Interleukin I pro duction The RDE can be used to stimulate the production of lymphokines released by macrophages. Interleukin-l is
a soluble immunoregulator released by macrophages which is responsible for the activation of lymphocytes
at the site of an infection. Interleukin-l plays a critical role as an amplifier of the immune response.
Murine macrophages were adhered to microtiter plates (1 x 106/well), each determination was made in triplicate. The first wells received 1 ml. of a 50 pjg/ml solution of standard endotoxin produced in accordance with the procedure described in the aforesaid co-pending application. 1 ml. of a 50Fg/ml solution of RDE in
accordance with the present invention was added to the second set of wells. Each agent was solubilized in M
199 medium with 5% FCS (fetal calf serum) 1 ml. M 199 medium with 5% FCS was added to the third set of
wells to serve as a control.
The plates were incubated at 37"C for 20 hours. The supernatant was removed and diluted to obtain a
solution having a 1.10 ration of supernatant to distilled water. The supernatant was tested for interleukin-l
production by the method of Gery, et al. Cellularlmmun. 64, 293 (1981).
The cells remaining after removal of the supernatant were lysed using 0.1% Triton X - 100. The resulting
solution was diluted with RPMI 1640 medium with 5% fetal calf serum at a 1:10 dilution ratio.
The diluted solution was tested for Interleukin-l production by measuring an augmentation of PHA inducted macrophage uptake of H3-thymidine as described in Gery et al supra. The results are shown in
Table I.
TABLE I
Test Supernatant Lysate
Material Response Response
(50 g/ml) (1:10 Dilution) (1:10 Dilution)
Endotoxin 31,137 i 1,721 51,695 + 2797
Standard RDE 16,7821,295 1,295 66,1782332 Control 3,323 31 12,153 497
As shown in Table I, Interleukin-l production from RDE of the present invention in the lysed cells greatly exceeded the Interleukin-l production from the standard endotoxin extract.
The same assay was conducted using human monocytes nstead of murine macrophages.
The results are as follows:
TABLE IA
Test Supernatant Lysate
Material Response Response (10ig/mA) (1:50 Dilution) (1:50 Dilution)
Endotoxin 42,418 1763 51,821 t 1348
Standard
RDE 17,910 1983 50,626813 Control 1,693 289 15,173 + 1,292 (3) Macrophage activation
RDE of the present invention also stimulates macrophages as measured by the ability of macrophages to phagocytize (engulf) fluorescent beads.
1 x 106 peritoneal exudate cells were mixed with 5 J; of a solution of a test material containing standard endotoxin, RDE of the present invention and saline as a control to respectively form three test solutions.
Each of the solutions contained 1 sLg of the test material and 20 pe of a fluorescent bead suspension. The test solutions were placed on individual microscope slides and then incubated for 90 minutes at 37 C.
After incubation, the slides were observed under a fluorescent microscope. By visual observation, the number of cells which phagocytosed the fluorescent beads was determined as well as the number of beads/cell.
The phagocytic index was calculated in accordance with the formula:
Phagocytic index = % cells Dhagocvtosing x number of
beads/100 cells
1000 and the results of the two experiments are shown in Table II.
TABLE II Phagocyticlndex * Expt 1 Expt 2
Endotoxin Standard 5.0 3.6
RDE 5.4. 4.1
Control 1.0 0.5
As can be seen from Table II. the phagocytic index for RDE of the present invention was significantly greater than that of standard endotoxin, thereby establishing that RDE is an exceedingly potent stimulator of macrophages.
(4) Adjuvant activity
To further establish the use of RDE as a stimulator of the immune of warm blooded animals, RDE was tested for adjuvanticity as determined by its ability to augment the immune response to sheep red blood cells (SRBC) by measuring the ability of antibodies to lyse the sheep red blood cells.
Three test materials were prepared. Each contained 1 x 107 amount of SRBC. Test material #2 further contained 20 mcgs. of standard endotoxin + SRBC while test material #3 contained 20 mcgs. of RDE in accordance with present invention + SRBC.
Test materials were injected interperitoneally into strain BALB/C mice. After 4-5 days, the test animals were sacrificed and the spleens removed and ground in a tissue grinder. A standard cell suspension of each spleen was made using a haemocytometer and each of the above suspensions were placed on slides along with the target SRBC, media, and agar.
The slides were incubated for 2 hours at 37 C and Guinea Pig sera was added as a complement source to each of the slides followed by incubation for 30 minutes at370C.
Thereafter, the slides were examined to determine the quantity of plaque forming cells, which are areas in which antibodies destroyed the SRBC cells with the aid of the complement found in the Guinea Pig sera.
The results are shown in Table Ill.
TABLE Ill
Test Material PFCI2x 105 Spleen Cells
SRBC 88
SRBC + Endotoxin Standard 165
SRBC + RDE 219
As can be seen from Table Ill, the number of plaque forming cells resulting from the use of RDE compared with standard endotoxin was significantly higher which establishes that RDE is a potent adjuvant.
The RDE as used in the present invention may be administered in combination with a pharmaceutically acceptable medium such as saline or an oil-droplet emulsion. The aforesaid composition may be stabilized as, for example, by a lyophilization procedure and then reconstituted without loss of potency.
As described above, the composition for treatment of warm blooded animals and humans may be used in the form of an oil droplet emulsion. The amount of oil used is in the range of between about 0.5 and 3.0 percent by volume based on the total volume of the composition. It is preferred to use between about 0.75 and 1.5 percent by volume of the oil. Examples of suitable oils include light mineral oil, squalane, 7-n-hexyloctadecane, Conoco superoil and Drakeol 6 VR mineral oil (produced by the Pennreco Company,
Butler, Pennsylvania).
The homogenized oil containing mixture is then combined with a detergent which may optionally be dissolved in a saline solution prior to mixing. The amount of detergent is typically between about 0.02 and 0.20 percent by volume and preferably between about 0.10 and 0.20 percent by volume based on the total volume of the composition. Any common detergent material may be used including Tween-80, and Arlacel (produced by the Atlas Chemical Company).
The mixture resulting from the addition of detergent is then homogenized to form a suspension which has a high percentage of oil droplets coated with RDE as determined by observation under a microscope.
The amount of RDE in a single injection is between 5 and 500 > 9, preferably between 10 and 1009 (per total body weight of a 70 kg human adult.
1-3 injections are administered over a period of about 2 months.
The RDE composition used in the present invention exhibits significantly less pyrogenic activity than a composition containing standard endotoxin as evidenced by the following example.
Three New Zealand strain rabbits, were injected (into an ear vein) with a composition containing standard endotoxin. The amount of standard endotoxin necessary to cause an increase in body temperature of at least 0.46so in 50% of the test population was determined over a period of 3 hours using a rectal thermometer.
Three other test rabbits were also injected with a composition containing RDE and the same pyrogenic activity test was made. The results are shown in the following Table IV.
TABLE IV
Pyrogenicity
Test Material RabbitActivity*
(in ijg 11kg)
Endotoxin Standard 0.012
RDE 10 (i.e. no fever at
highest does = 10 g) *The dose necessary to cause
afebrile (fever) response
of greater than 0.46"C in
50% of a test population.
As shown in Table IV, standard endotoxin produced a fever response in 50% of the test animals at a dosage of 0.012 Fg/kg. RDE however, did not produce a fever response at > 10 > g/kg, which is 850 times the dose level of the standard endotoxin.
Claims (6)
1. A composition capable of producing an effective adjuvant response or stimulating the immune response of a warm blooded animal comprising an effective amount of a composition comprising refined detoxified endotoxin having no detectable 2-keto-deoxyoctanoate, between about 350 and 475 n moles/mg of phosphorus and between about 1700 and 2000 n moles/mg of fatty acids, in combination with a pharmaceutically acceptable carrier.
2. A composition according to claim 1 wherein said effective amount is between about 5 and 500 pwg/kg.
3. A composition according to claim 2 wherein said effective amount is between about 10 and 100 Fglkg.
4. A composition according to claim 1 which is in lyophilized form.
5. A composition according to claim 1 which is an oil droplet emulsion.
6. A composition capable of producing an effective adjuvant response or stimulating the immune response of a warm blooded animal substantially as described herein.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US52696783A | 1983-08-26 | 1983-08-26 |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8420612D0 GB8420612D0 (en) | 1984-09-19 |
GB2147806A true GB2147806A (en) | 1985-05-22 |
GB2147806B GB2147806B (en) | 1986-10-22 |
Family
ID=24099553
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08420612A Expired GB2147806B (en) | 1983-08-26 | 1984-08-14 | Refined detoxified endotoxin compositions |
Country Status (22)
Country | Link |
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JP (1) | JPS6072825A (en) |
KR (1) | KR880002223B1 (en) |
AT (1) | AT389228B (en) |
AU (1) | AU554039B2 (en) |
BE (1) | BE900377A (en) |
CA (1) | CA1225592A (en) |
CH (1) | CH660125A5 (en) |
DE (2) | DE3448164C2 (en) |
DK (1) | DK389384A (en) |
ES (1) | ES8606883A1 (en) |
FI (1) | FI843204A (en) |
FR (1) | FR2550945B1 (en) |
GB (1) | GB2147806B (en) |
HU (1) | HU191713B (en) |
IL (1) | IL72675A (en) |
IN (1) | IN157910B (en) |
IT (1) | IT1177974B (en) |
NL (1) | NL192326C (en) |
NO (1) | NO843243L (en) |
NZ (1) | NZ209233A (en) |
SE (1) | SE8404090L (en) |
ZA (1) | ZA846309B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2161381A (en) * | 1984-07-12 | 1986-01-15 | Ribi Immunochem Research Inc | Detoxified endotoxin compositions |
WO2002076483A2 (en) * | 2001-03-28 | 2002-10-03 | Danelia Nodar A | Bacteriophage preparation |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4803070A (en) * | 1986-04-15 | 1989-02-07 | Ribi Immunochem Research Inc. | Immunological emulsion adjuvants for polysaccharide vaccines |
US4806352A (en) * | 1986-04-15 | 1989-02-21 | Ribi Immunochem Research Inc. | Immunological lipid emulsion adjuvant |
KR100868443B1 (en) * | 2002-05-27 | 2008-11-11 | 주식회사 포스코 | An apparatus for bending a strip packing sheet |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2122083A (en) * | 1982-05-26 | 1984-01-11 | Ribi Immunochem Research Inc | Anti-tumour micro-organism obtained products |
GB2122204A (en) * | 1982-05-26 | 1984-01-11 | Ribi Immunochem Research Inc | Refined detoxfied entoxin (lipid a) and anti-tumour compostions thereof |
GB2122084A (en) * | 1982-05-26 | 1984-01-11 | Ribi Immunochem Research Inc | Anti-tumour micro-organism obtained products |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2160326B1 (en) * | 1971-11-19 | 1975-02-07 | Anvar | |
BE793260A (en) * | 1971-12-24 | 1973-06-22 | Pasteur Institut | IMMUNOSTIMULANT AGENT, MEDICINES CONTAINING IT AND METHOD FOR MANUFACTURING SUCH IMMUNOSTIMULANT AGENT |
NL7507376A (en) * | 1974-06-20 | 1975-12-23 | Anvar | PROCESS FOR THE PREPARATION OF BACTERIAL PREPARATIONS WITH ANTI-TUMOR, ANTIVIRAL AND ADJUVANS ACTIVITIES. |
FR2393065A1 (en) * | 1977-05-31 | 1978-12-29 | Merieux Inst | PROCESS FOR SEPARATION OF LIPIDS FROM BACTERIAL ENDOTOXINS AND IN PARTICULAR FROM BORDETELLA PERTUSSIS ENDOTOXIN |
-
1984
- 1984-08-10 CA CA000460820A patent/CA1225592A/en not_active Expired
- 1984-08-13 DK DK389384A patent/DK389384A/en not_active Application Discontinuation
- 1984-08-14 ZA ZA846309A patent/ZA846309B/en unknown
- 1984-08-14 GB GB08420612A patent/GB2147806B/en not_active Expired
- 1984-08-14 IN IN567/CAL/84A patent/IN157910B/en unknown
- 1984-08-14 FI FI843204A patent/FI843204A/en not_active Application Discontinuation
- 1984-08-14 IL IL72675A patent/IL72675A/en not_active IP Right Cessation
- 1984-08-14 ES ES535124A patent/ES8606883A1/en not_active Expired
- 1984-08-14 NO NO843243A patent/NO843243L/en unknown
- 1984-08-14 SE SE8404090A patent/SE8404090L/en not_active Application Discontinuation
- 1984-08-15 NZ NZ209233A patent/NZ209233A/en unknown
- 1984-08-16 NL NL8402515A patent/NL192326C/en not_active IP Right Cessation
- 1984-08-17 BE BE0/213506A patent/BE900377A/en not_active IP Right Cessation
- 1984-08-21 CH CH4001/84A patent/CH660125A5/en not_active IP Right Cessation
- 1984-08-21 AU AU32215/84A patent/AU554039B2/en not_active Expired
- 1984-08-23 DE DE3448164A patent/DE3448164C2/de not_active Expired
- 1984-08-23 FR FR8413133A patent/FR2550945B1/en not_active Expired
- 1984-08-23 HU HU843169A patent/HU191713B/en unknown
- 1984-08-23 DE DE19843431058 patent/DE3431058A1/en active Granted
- 1984-08-24 IT IT48757/84A patent/IT1177974B/en active
- 1984-08-25 KR KR1019840005189A patent/KR880002223B1/en not_active IP Right Cessation
- 1984-08-25 JP JP59175877A patent/JPS6072825A/en active Granted
- 1984-08-27 AT AT0273384A patent/AT389228B/en not_active IP Right Cessation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2122083A (en) * | 1982-05-26 | 1984-01-11 | Ribi Immunochem Research Inc | Anti-tumour micro-organism obtained products |
GB2122204A (en) * | 1982-05-26 | 1984-01-11 | Ribi Immunochem Research Inc | Refined detoxfied entoxin (lipid a) and anti-tumour compostions thereof |
GB2122084A (en) * | 1982-05-26 | 1984-01-11 | Ribi Immunochem Research Inc | Anti-tumour micro-organism obtained products |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2161381A (en) * | 1984-07-12 | 1986-01-15 | Ribi Immunochem Research Inc | Detoxified endotoxin compositions |
WO2002076483A2 (en) * | 2001-03-28 | 2002-10-03 | Danelia Nodar A | Bacteriophage preparation |
WO2002076483A3 (en) * | 2001-03-28 | 2003-05-01 | Nodar A Danelia | Bacteriophage preparation |
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