Drug – bio-affecting and body treating compositions – Lymphokine
Patent
1985-10-16
1988-02-09
Kight, John
Drug, bio-affecting and body treating compositions
Lymphokine
424 92, 424 93, 435 68, 435863, 435822, A61K 3904
Patent
active
047241446
DESCRIPTION:
BRIEF SUMMARY
This invention relates to immunotherapeutic agents useful in the immunotherapy of mycobacterial disease, especially tuberculosis and leprosy.
The eradication of mycobacterial diseases such as tuberculosis and leprosy by effective treatment is still a primary objective particularly in disease endemic areas such as third world countries of Asia, Africa and South East Asia. Modern drug treatment of these diseases consists of chemotherapy with, for example, rifampicin and isoniazid in the case of tuberculosis and clofazimine and sulphones in the case of leprosy.
Chemotherapy, though effective in killing rapidly metabolising bacilli, is very slow to eliminate "persisters", and this necessitates continuation of treatment for 9 months to a year in the case of tuberculosis, and 5 years or more in the case of leprosy. `Persisters` are metabolically inactive microorganisms which can survive long exposure to a drug, only becoming susceptible when they start to multiply.
We have now found that the mycobacterium, M. vaccae, is especially effective for the immunotherapy of mycobacterial disease, especially tuberculosis and leprosy. Experiments have shown that suspensions containing killed M. vaccae in excess of 10.sup.8 microorganisms per ml of diluent can be effective in eliminating "persisters" within a short period of time, usually 1 or 2 months. In addition, vaccines based on M. vaccae are easy to manufacture at low cost since M. vaccae can be cultivated in simple media, unlike some other species of mycobacteria, for example M. leprae, which can only be cultivated in armadillo tissues which are expensive and not easily obtainable.
The present invention therefore provides an immunotherapeutic agent comprising antigenic material derived from Mycobacterium vaccae. The antigenic material is conveniently, and therefore preferably, dead cells of M. vaccae, e.g. cells which have been killed by irradiation. The immunotherapeutic agent normally comprises more than 10.sup.8 microorganisms per ml of diluent, and preferably from 10.sup.8 to 10.sup.11 killed M. vaccae microorganisms per ml of diluent. The invention includes within its scope antigenic material from M. vaccae for use in therapy in the treatment of mycobacterial disease, e.g. tuberculosis or leprosy, preferably as an adjunct to chemotherapy.
The diluent may be pyrogen-free saline for injection alone, or a borate buffer of pH 8.0. The diluent should be sterile. A suitable borate Buffer is:
The preferred strain of M. vaccae is one denoted R877R isolated from mud samples from the Lango district of Central Uganda (J. L. Stanford and R. C. Paul, Ann. Soc. belge Med, trop. 1973, 53, 141-389). The strain is a stable rough variant and belongs to the aurum sub-species. It can be identified as belonging to M. vaccae by biochemical and antigenic criteria (R. Bonicke, S. E. Jahasz., Zentr albl. Bakteriol. Parasitenkd. Infection skr. Hyg. Abt. 1, Orig., 1964, 192, 133). M. vaccae is believed to be closely similar antigenically to M. leprae (J. L. Stanford et al, British Journal of Experimental Pathology, 1975, 56, 579).
The strain denoted R877R has been deposited at the National Collection of Type Cultures (NCTC) Central Public Health Laboratory, Colindale Avenue, London NW9 5HT, United Kingdom on Feb. 13th, 1984 under the number NCTC 11659.
For the preparation of the immunotherapeutic agent, the microorganism M. vaccae may be grown on a suitable solid medium. A modified Sauton's liquid medium is preferred (S. V. Boyden and E. Sorkin., J. Immunol, 1955, 75, 15) solidified with agar. Preferably the solid medium contains 1.3% agar. The medium inoculated with the microorganisms is incubated to enable growth of the microorganisms to take place, generally at 32.degree. C. for 10 days. The organisms are harvested, then weighed and suspended in a diluent. The diluent may be saline but it preferably also contains a surfactant such as Tween 80. 1 part Tween 80 is preferably used in 300 parts saline. The suspension is diluted with the saline/Tween 80 diluent to give 100 mg of microorgani
REFERENCES:
patent: 3849551 (1974-11-01), D'Antonia
Navalker et al, Abst. Int. J. Lepr. Other Myabart Dis., 1980, 48(4), pp. 388-396.
Baker et al, Abst. Immunol., 1981, 44(3), pp. 593-598.
Leprosy Review 47, pp. 87-91, 1976.
F. M. Collins et al., "Immune Response to Persistent Mycobacterial Infection in Mice", Infection and Immunity, vol. 20, No. 2, May 1978, pp. 430-438.
S. R. Watson et al., "Delayed Hypersensitivity Responses in Mice and Guinea Pigs to Mycobacterium Lebrae, Mycobacterium Vaccae and Mycobacterium Nonchromogeni cum Cytoplasmic Proteins", Biological Abstracts, vol. 69, No. 1, 1980, p. 306, abstract 2847, Infect. Immun. 25(1), 229, 236, 1979.
F. M. Collins et al., "Fernandez and Mitsuda Reactivity in Guinea Pigs Sensitized with Heat-Killed Mycobacterium Leprae: Persistence and Specificity of Skin Reactivity to Soluble and Particulate Antigens", Biological Abstracts, vol. 78, No. 3, 1984, p. 2213, abstract 19506, Int. J. Lepr. 51(4): 481-489, 1983.
Rook Graham A. W.
Stanford John L.
Draper Garnette D.
Kight John
University College London
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