WO1986004243A1 - Procede et produit ameliorant la reaction d'un anticorps en circulation - Google Patents

Procede et produit ameliorant la reaction d'un anticorps en circulation Download PDF

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Publication number
WO1986004243A1
WO1986004243A1 PCT/US1986/000105 US8600105W WO8604243A1 WO 1986004243 A1 WO1986004243 A1 WO 1986004243A1 US 8600105 W US8600105 W US 8600105W WO 8604243 A1 WO8604243 A1 WO 8604243A1
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WIPO (PCT)
Prior art keywords
vaccine
cells
penicillin
adjuvant
minutes
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Application number
PCT/US1986/000105
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English (en)
Inventor
Chin Chuan Chang
Yun-Yen Tsong
Harold A. Nash
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The Population Council, Inc.
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Publication date
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Publication of WO1986004243A1 publication Critical patent/WO1986004243A1/fr

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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
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • 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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • 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
    • A61K2039/55505—Inorganic adjuvants
    • 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
    • A61K2039/55588—Adjuvants of undefined constitution
    • A61K2039/55594—Adjuvants of undefined constitution from bacteria
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a novel method for enhancing circulating antibody response and to a novel vaccine containing cell material of Strepto ⁇ coccus hemolyticus as an adjuvant.
  • a defensive reaction called the immune response is evoked when a macromolecule foreign to a given animal gains entrance into its blood or tissues.
  • the foreign macromolecule or antigen binds first to a T lympho ⁇ cyte, then the immunological information is passed to the B lymphocyte, causing it to undergo development into a plasma cell, which in turn produces an antibody to the antigen.
  • the antibody circulates throughout the blood or tissues until it recognizes and combines with the antigen which elicited its formation, thereby hastening its destruction and elimination and fre ⁇ quently immediately rendering the antigen inactive. It has been well established that stimulation of such immuno-competent cells will lead to enhanced antibody production. Also, maintenance of the antigen level contributes to prolongation of antibody produc ⁇ tion.
  • One way of enhancing the immune response is to prepare a vaccine consisting of an antigen together with a substance, which for reasons frequently not well understood, increases and prolongs antibody production.
  • One particularly well known adjuvant is the water-in-oil emulsion developed by Dr. Freund.
  • Dr. Freund When Freund's adjuvant is combined with an antigen and then injected into an animal, the immune response elicited is generally much greater and of longer duration than the immune response elicited from the antigen alone.
  • One of the disadvantages frequently associated with the use of Freund's adjuvant is a pyrogenic response in the subject animal. Another disadvantage of
  • Freund's adjuvant is that it causes skin eruptions and lesions because of its nonabsorbability by the tissues. Still another disadvantage of Freund's water-in-oil emulsion is the tendency of the emulsion to be unstable upon storage.
  • the initial exposure of an animal to an antigen usually evokes a primary response, in which circulat ⁇ ing antibodies are in most cases detectable after 1 to 30 days more.
  • the time needed to attain maximal con- centration of antibodies, and the duration of peak titer vary with the antigens and methods of immuniza ⁇ tion.
  • the concentration of circulating antibodies may begin to decline within several days after reaching -the maximum level.
  • the adjuvant activity of mycobacteria is now interpreted to be due largely to a complex glycolipid.
  • the immunogenic-enhancing properties of the myco ⁇ bacteria have been duplicated by a synthesized glyco- peptide called, generally, muramyl dipeptide, and more particularly N-acetyl-muramyl-1-alanyl isoglutamine.
  • Antigens combined with adjuvants of muramyl dipeptide usually have low activity unless introduced into the host animal via a water-in-oil emulsion.
  • 3,477,914 to Oka oto et al. describes processes for treating cells of Streptococcus hemolyticus whereby anti-tumor activity is retained while causing the cells to have no virulence and no hemolytic activity.
  • a product prepared according to the teachings of this patent is available from Chugai Pharmaceutical Co. Ltd. under the trade names OK-432 or Picibanil.
  • the product marketed under the trade names OK-432 and Picibanil contains penicillin used in treating the Streptococcus hemolyticus cells; Banil is a designation for a non- marketed product similar in all respects to Picibanil except that it is substantially penicillin- ee.
  • Streptococcus hemolyticus cells treated by cultivation in the presence of penicillin results in enhancement of the circulating antibody response to particular antigens.
  • the cells of Streptococcus hemolyticus thus treated are combined with known anti ⁇ gens and other known adjuvants to form a vaccine which unexpectedly enhances circulating antibody concentra ⁇ tion by from 3 to 14 fold, as compared with control formulations, based on tests conducted in rabbits.
  • the vaccine of this invention provides the desired enhancement with simultaneous, same site administra ⁇ tion of the antigen and adjuvant.
  • booster response is enhanced by using the cell prepa ⁇ ration in the primary injection, irrespective of whether it is used in a booster injection, and pro ⁇ vides enhancement in the booster.
  • the initial innoculum used is lyophilized cells of a nearly avirulent strain Su ATCC 21060 of Strep ⁇ tococcus hemolyticus preserved in an ampule under reduced pressure in meat-infusion broth.
  • the cells are cultivated serially and used within the fifth or sixth subculture in the broth as seeding material. The cultivation is performed by incubation at 37°C. and the culture is maintained at 2-5°C. during inter ⁇ vals between transfers.
  • the meat-infusion broth is prepared according to directions for Medium, General Test Procedures in the Japanese Biological
  • the pH of the broth is adjusted to between 7.3 and 7.5.
  • the broth is sterilized at
  • the yeast extract medium is prepared by dissolv- ing 50 g. of yeast extract in 800 ml of water, with the pH of the solution adjusted to 7.3 to 7.5. It is then heated at 110°C. for 10 minutes, filtered using Toyo Filter Paper No. 5C (Toyo Roshi Kaisha, Ltd.) and sufficient purified water is added to make 1000 ml. The medium is then filtered through a membrane filter with a 0.45 pore size (HAWP, Millipore -Corporation) to remove the fine insoluble materials, and then steri ⁇ lized at 121°C. for 30 minutes under pressure of 1 Kg/cm 2 . The bacterial strain is innoculated into meat- infusion broth and cultivated at 37°C. for 20 to 24 hours. One volume of the resulting culture is added to 20 volumes of yeast extract medium, prepared as described above, and the mixture is cultivated at 37°C. for 20 hours to obtain a final culture.
  • HAWP 0.45 pore size
  • the bacterial cells are collected from the final culture by centrifugation and suspended in physiologi ⁇ cal saline.
  • One volume of 10% (W/V) hydrogen peroxide solution is added to 10 volumes of cell suspension in the saline solution and mixed. The mixture is allowed to stand for 30 minutes at 2°C. and the cells then collected by centrifugation.
  • the cells are resuspended in physiological saline and a cell concentration that will give an absorbance between 0.33 and 0.36 at 390 m ⁇ as determined with a Hitachi Spectrophotometer Model 202-20, using a sample made by diluting one volume of the cell suspension with 19 volumes of physiological saline.
  • one volume of a solution of potassium salt of penicillin G (1.6 x 10 units/ml) is added to five volumes of the cell suspension in BBM, the suspension mixed, and then incubated at 37°C. for 20 minutes. The suspension is then heated to 45°C. for 30 minutes, and the suspension cooled.
  • the cells are collected by centri ⁇ fugation and resuspended in the same amount of a solu- tion made by combining 5 vol. of BBM with penicillin and 1 vol. of physiological saline. An equal amount of 1% DL-methionine solution is added and mixed to obtain a cell suspension for final bulk.
  • the substantially penicillin-free product desig- nated Banil is obtained using a modification of the above process wherein the cells collected after the penicillin treatment and incubation steps are given three additional washing steps using physiological saline. While the procedure described above for preparing Picibanil and Banil produce preferred cell prepara ⁇ tions of Streptococcus hemolyticus for use according to this invention, other procedures as described in U.S. patent No. 3,477,914 can be used.
  • the cells can be initially incubated in the presence of penicillin at a temperature in the range of 30-80°C. for at least 10 minutes where the concentration of penicillin is greater than 25,000 units per ml. The temperature of incubation is then increased to within the range of 38-50°C. for an additional time of from 20-60 minutes. Thereafter the culture is cooled.
  • the present invention will be described in terms of an antipregnancy vaccine based on beta hCG.
  • this antigen is relatively ineffective in raising antibody response when injected by itself, it is normally conjugated with a subject-compatible immu- nogenic carrier, as described in U.S. patent No. 4,161,519 to Talwar.
  • a subject-compatible immu- nogenic carrier as described in U.S. patent No. 4,161,519 to Talwar.
  • tetanus toxoid is tetanus toxoid.
  • this conjugate will be termed ⁇ -hCG-TT.
  • the vaccines of this invention are described in terms of the use of S-hCG as the antigen of interest, as well as rubella and ovine luteinizing hormone, it is recognized that Banil and Picibanil are also useful as adjuvants in other vaccines, such as those for tetanus, diphtheria, influenza, cholera, hepatitis, as well as animal vaccines for diseases such as hoof and mouth disease, distemper, leptospiro- sis, brucella abortus, and animal-vectored diseases such as trypanosomiasis, yellow fever, malaria and plague.
  • the vaccines and methods of this inven ⁇ tion include antigens of viral, parasite, bacterial and hormone origin.
  • a preferred group of protein hormone antigens include ⁇ -hCG and ovine luteinizing hormone.
  • S-hCG Human chorionic gona ⁇ dotropin
  • ⁇ -hCG was incu ⁇ bated at 40°C. for 1 hour with 8 M freshly prepared urea solution that had been purified on a mixed cation-anion exchange resin column, specifically a bed of equal quantities of Dowex-1 X-8 and Dowex-50 X-4, 200 mesh. The column size was 2 x 40 cm.
  • the beta subunits were first dis ⁇ sociated and then separated by the method described by Morgan and Canfield, Endocrinology . Vol.
  • the mixture was passed through ion exchange columns and Sephadex columns repeatedly to obtain the dissociated beta subunit with minimal contamination of the whole human chorionic gonadotropin molecule or its alpha subunit.
  • the reaction product was dialyzed extensively against 1 M phosphate buffered saline, (PBS) (pH 7.5) at a temperature of 10°C.
  • the product hereinafter ⁇ -hCG- TT, was collected in a sterile tube using a Millipore filter and syringe assembly.
  • the product was stored at 4°C.
  • the product was adsorbed on aluminum hydrox ⁇ ide using sterile 10% alum and then partially neutra ⁇ lized by adding sterile 10% sodium bicarbonate until a maximum precipitate was obtained.
  • the mixture was centrifuged at 3000 rpm for 10 minutes. The procedure of adding sodium bicarbonate until a maximum precipi ⁇ tate formed and then centrifuging the mixture was repeated two times.
  • the emulsions contained PBS, Arlacel A and peanut oil in the ratio 50:7:43.
  • Levamisole and thymic factor were suspended in 2% carboxymethylcellulose in PBS and injected subcuta- neously separately from the vaccine formulations con ⁇ taining Lipomal, a soy phosphatide preparation (Huhtamaki Oy/Leiras Pharmaceuticals, Turku, Finland) or Intralipid, an oil-in-water emulsion for intra ⁇ venous use (Cutter Laboratories, Emeryville, California) . Equal amounts of Lipomal and PBS were used.
  • the Intralipid was prepared using 2.5 ml saline, 0.1 ml Tween 80-sorbitan monooleate (Sigma Chemicals) and 4.6 ml Intralipid. ⁇ -hCG-TT on alumi ⁇ num hydroxide was added to the vehicles containing Lipomal and Intralipid to form a suspension.
  • the effectiveness of the antisera in neutralizing the biological activity of hCG has been determined in the rat uterine weight assay.
  • a total dose of 0.6 I.U. hCG reference preparation (NIH, CR- 121) in 1% bovine serum albumen (BSA) was prepared as the standard.
  • the anti-serum or the antiserum diluted with 1% BSA was mixed with an equal volume of 0.6 I.U. hCG solution so that each animal received a total volume of 1.5 ml.
  • the solution was incubated at room temperature for 2 hours before initial injection.
  • Tests for pyrogenic activity were made by measur ⁇ ing body temperature of the rabbits rectally with a thermister probe and a Yellow Springs Instrument Company telethermometer one hour before and 1, 2, and 3 hours after dosing. The preparation was judged to be pyrogenic if the average maximum temperature increase over pretreatment was 0.6°C. or more.
  • the neutralizing capacity of the control group receiving ⁇ -hCG-TT on Al(OH) 3 in the same experiment is taken as "1".
  • the neutralizing capacity was expressed as the reciprocal of the dilution producing 50 percent inhibition of hCG- stimulated uterine weight gain.
  • Formulation in a water-and-oil emulsion resulted in 3-fold increases in titers over those found fol ⁇ lowing vaccination with ⁇ -hCG-TT on Al(OH) 3 in aqueous suspension.
  • Formulation in liposomes or in an oil- in-water emulsion did not result in increased titers.
  • Table III results obtained when the amine adjuvant, Avridine, was formulated in different ways. No significant enhancement of response over that of ⁇ -hCG-TT on Al(OH) 3 alone was obtained by the use of this adjuvant in oil-in-water or water-in-oil emulsions. Moderate enhancement was achieved when the adjuvant was used with ⁇ -hCG-TT on Al(OH) 3 incor ⁇ porated in liposomes.
  • the above work demonstrates the effectiveness of the streptococcal preparation OK-432 in increasing circulating antibodies in accordance with this inven ⁇ tion.
  • the increment in titers resulting from OK-432 use is comparable to that observed with use of a muramyl dipeptide analog in a water-in-oil emulsion with the same antigen. It is far less than the incre ⁇ ment observed with Freund's complete adjuvant (FCA) but unlike FCA does not cause overt local reactions. It has the additional advantages as a vaccine compo ⁇ nent of not requiring formulation in a water-in-oil emulsion to attain high activity as has proved neces ⁇ sary with the muramyl dipeptide analogs.
  • the viral concentrates were then inactivated with ether and Tween 80 in accordance with the procedure of Norrby, E. Proc. Soc. Biol. Med. 1962, 11, 814. After inactivation the protein content was estimated by absorbance reading at 280 NM. The viral suspension was lyophilized.
  • Each animal receives 0.5 mg of rubella antigen.
  • the test group also receives 1.0 mg of Banil mixed with the antigen.
  • the vaccine is brought to 1 ml volume with distilled water.
  • the animals are bled at 2 and 5 weeks post- immunization.
  • the rubella antibody titers are deter- mined by enzyme-linked immunosorbent assay (ELISA) ,
  • Example II Five rabbits of the type described in Example I were used in each of three groups. Three primary vaccinations were given, spaced two weeks apart. The ⁇ -hCG was combined with tetanus toxoid in the manner described in Section B of Example I above, and was adsorbed on Al(OH)... The dose given was calculated to provide 100 ⁇ g of ⁇ -hCG at each vaccination. The same dosage was used at all primary and booster injections.
  • Group B received 0.5 mg OK-432, in the first vaccination, 1.0 mg, OK-432 in the second vaccination, and 2.0 mg. in the third. Further, in the primary series, Group C received 0.166, 0.33 and 0.66 mg OK-432 in each of the 3 successive vaccinations.
  • Booster injections to Group A were of same composition as the primary vac ⁇ cination. The first two booster injections to Group B contained 1 mg of OK-432, and the third booster injec ⁇ tion to Group C contained 1 mg of OK-432.
  • the first booster injection was given 4.5 months after the last primary injection, and the interval between booster injections was 2 months.
  • Sera for antibody determinations were taken 2, 4, 6 and 8 weeks after the last primary vaccination. Titers obtained at these time intervals were averaged to determine mean response.
  • Booster response is enhanced so long as OK- 432 is used in the primary vaccination, irrespective of whether it is included in the booster injection.
  • Example I Five rabbits of the type used in Example I were used in each group. Three primary vaccinations were given, spaced two weeks apart. Booster injections were given 10 weeks after the last primary injection. Antigen used was ⁇ -hCG-TT, as prepared in Example I, in amount to deliver 100 ⁇ g of ⁇ -hCG in each injection. Except for the booster injections given in Groups M and 0, the antigen was adsorbed on Al(OH) 3 , following the procedure outlined in Example I. The diagram given below shows the protocol: Protocol Group N Group M Group 0 Primary Booster Primary Booster Primary Booster Al(OH) 3 + + + + + + + + + + + + + + + + + + +
  • the dose of Banil in the booster injection to Group N was one mg per rabbit.
  • Antibody titers on sera taken after the primary vaccinations and after the booster vaccinations are tabulated below in Table V.
  • a series of tests were conducted to determine if the inclusion of adjuvants supplementary to Al(OH) 3 in the primary immunization series enhances booster response.
  • the tests were designed to determine if there is advantage in including a murabu- tide analog (MDP) in a water-in-oil emulsion in the booster injection; to determine if there is advantage in including Banil in the booster injection; and to determine if the omission of Al(OH)_ from the booster injection is deleterious to antibody response.
  • MDP murabu- tide analog
  • Example II Five rabbits of the type used in Example I above was used in each group. Three primary injections were given, spaced two weeks apart. Antigen used was ⁇ - hCG-TT, prepared as in Example I above. In all except for the booster injection given to one group, the antigen was adsorbed on Al(OH) 3 following the proce ⁇ dure of Example I. Dose was calculated to give 100 ⁇ g of ⁇ -hCG-TT, and all vaccinations were intramuscular. The urabutide was used as described in Nash et al. (J. Reprod. Immunol. 7 (1985) 151-162) using Span and Tween as emulsifying agents. Dose per rabbit was 250 ⁇ g.
  • the Banil was added to an aqueous suspension of the antigen in amount to deliver one mg per rabbit.
  • Blood samples for antibody titers were taken 2, 4, 6 and 8 weeks following the last primary vaccina ⁇ tion.
  • Mean response for each rabbit was obtained by averaging the titers obtained on samples taken at these four sampling times.
  • Antibody titers in serum samples taken after the primary vaccinations and after the booster injections are shown in Table VI.
  • Banil in the primary immuni ⁇ zation series has enhanced the primary response.
  • the mean response of the 20 animals receiving ⁇ -hCG-TT on Al(OH) 3 was 2332 ⁇ 173. That of the 10 animals also receiving Banil in the primary injections was 8666 +.1702.
  • the inclusion of murabutide in the primary series also caused a significant increment increase in the primary response
  • Picibanil used as a supplementary adjuvant in an aqueous suspension is effective in increasing the antigenicity of not only ⁇ -hCG-TT on A1(0H)- vaccine but also oLH ⁇ -TT on Al(OH) 3 vaccine, although the magnitude of enhancement of antibody titer of the latter was not as high as the former vaccine.

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  • Mycology (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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Abstract

Vaccin contenant un antigène et un adjuvant comprenant des cellules de Streptococcus hemolyticus ayant été traitées avec de la pénicilline. L'adjuvant améliore la réaction de l'anticorps en circulation contre l'antigène.
PCT/US1986/000105 1985-01-25 1986-01-24 Procede et produit ameliorant la reaction d'un anticorps en circulation WO1986004243A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US69479885A 1985-01-25 1985-01-25
US694,798 1985-01-25
US82016386A 1986-01-21 1986-01-21
US820,163 1986-01-21

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WO1986004243A1 true WO1986004243A1 (fr) 1986-07-31

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AU (1) AU5359186A (fr)
WO (1) WO1986004243A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5182109A (en) * 1988-04-08 1993-01-26 National Institute Of Health Vaccine preparation comprising a bacterial toxin adjuvant
US5688506A (en) * 1994-01-27 1997-11-18 Aphton Corp. Immunogens against gonadotropin releasing hormone

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3477914A (en) * 1966-03-08 1969-11-11 Chugai Pharmaceutical Co Ltd Treating method of streptococcus hemolyticus and the preparation containing the said microorganism

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3477914A (en) * 1966-03-08 1969-11-11 Chugai Pharmaceutical Co Ltd Treating method of streptococcus hemolyticus and the preparation containing the said microorganism

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Biological Abstracts, Volume 70, 1980, Philadelphia PA, (US) NAKAGAMI YOSHIZO et al.: "Adjuvant Immunotherapy with a Streptococcus Pyogenes Preparation (OK 432, Picibanil) in Urogenital Cancer Patients", see page 8314, Abstract No. 79672 & Invest Urol 17 (5): 386-389, 1980 *
Biological Abstracts, Volume 80, 1985, Philadelphia PA, (US) C.C. CHANG et al.: "Formulation of Potential Antipregnancy Vaccine Based on the beta-Subunit of Human Chorionic Gonadotropin 3 Evaluation of Various Vehicles and Adjuvants", see page 774, Abstract No. 25253 & J. Reprod. Immunol 7 (2), 163-170, 1985 *
CHEMICAL ABSTRACTS, Volume 97, No. 25, 20 December 1982, Columbus, Ohio, (US) WAKASUGI, HIRO et al.: "In Vitro Potentiation of Human Natural Killer Cell Activity by a Streptococcal Preparation, OK-432: Interferon and Interleukin-2 Participation in the Stimulation with OK-432", see page 668, Abstract No. 214026q & J. Natl. Cancer Inst. 1982, 69 (4), 807-12 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5182109A (en) * 1988-04-08 1993-01-26 National Institute Of Health Vaccine preparation comprising a bacterial toxin adjuvant
US5688506A (en) * 1994-01-27 1997-11-18 Aphton Corp. Immunogens against gonadotropin releasing hormone
US6132720A (en) * 1994-01-27 2000-10-17 Aphton Corp. Immunogens against gonadotropin releasing hormone
US6303123B1 (en) 1994-01-27 2001-10-16 Aphton Corporation Methods for the treatment of hormone-dependent tumors with immunogens against gonadotropin releasing hormone

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AU5359186A (en) 1986-08-13

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