Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-09-02
2002-08-13
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S924000
Reexamination Certificate
active
06433013
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a composition comprising a purified mycobacterial lipid cell-wall component or log or derivative thereof and a pharmaceutically acceptable excipient, medium, carrier or adjuvant and the use of the purified mycobacterial lipid cell-wall component or analog or derivative thereof and the composition containing it in the prevention, treatment and diagnosis of disease.
It has been known for a long time that BCG*) vaccination leads to the induction of a positive tuberculin skin test, resulting in delayed type hypersensitivity (DTH). This delayed hypersensitivity in turn has been considered to be indicative of the successful induction of protective immunity against tuberculosis and has led to the almost world-wide BCG immunization in the 1950s-1970s. This convenient test is in fact the only immunological criterion/parameter on which epidemiological assessments of the effectiveness of the immunization have been based.
BCG: (Bacillus of Calmette and Guerin) Calmette and Guerin attenuated a strain of
M. bovis
by passaging it 231 times over a period of 13 years through a medium containing glycerine and ox-bile.
This view is no longer generally accepted and many immunologists are of the opinion that
i) the induction of DTH is not directly related to the degree of protective immunity;
ii) the protective efficacy obtained in vaccination with BCG varies between 0 to 80% (Snider, 1994) and in addition
iii) BCG vaccination has detrimental side-effects being partially responsible for tissue destruction in patients, without offering sufficient protection (Fine, 1994).
The unsatisfactory results observed and reported in a number of countries with the BCG vaccine currently used for the prevention of the spread of tuberculosis (Dolin, Raviglione and Koch, 1994; Snider, 1994) could be explained by:
i) variations between BCG vaccines, which could be caused by strain variation or by differences between manufacturing processes;
ii) differences in pathogenesis of
Mycobacterium tuberculosis;
iii) differences in the exposure to the environmental mycobacteria. The environmental mycobacteria may act antagonistically or synergistically with BCG;
iv) genetic differences between population groups subjected to vaccination with BCG;
v) differences in nutrition and exposure to sunlight between various population groups;
vi) differences between designs of various studies;
vii) inadequacies of the criteria used for the evaluation of protective effects of vaccination with BCG.
Efforts directed at finding an effective vaccine capable of inducing long-lasting immunity have centered over the last decade on three main approaches:
i) identifying “protective” antigens and epitopes of
M. tuberculosis
presented by macrophages and recognized by human lymphocytes;
ii) developing a DNA-based vaccine with protective antigen and interleukin genes (Lowrie et al., 1994);
iii) identifying which types of cells of the immune system and which types of cytokines are involved in tuberculosis in order to manipulate their activity towards offering a cure or protection against tuberculosis.
SUMMARY OF THE INVENTION
According to one aspect of the invention there is provided a conjugate comprising an organic carrier and a purified lipid cell-wall component associated therewith, provided that if the organic carrier is a protein, it is not bovine serum albumin (BSA), gelatin, keyhole limpets haemocyanin or the CD
1
molecule.
The organic carrier may be a protein excluding bovine serum albumin (BSA), gelatin, keyhole limpets haemocyanin and the CD
1
molecule.
The protein may be a microbial protein. More specifically, it may be a modified bacterial protein and may be derived from a bacterium from the genus Mycobacterium, Corynebacterium, Nocardia or Rhodococcus. It may be a heat-shock protein, such as heat-shock protein 60 (HSP60) or heat-shock protein 65 (HSP65), or it may be a serum protein from an animal. The animal may have a mycobacterial infection, such as a
Mycobacterium tuberculosis
infection. The animal may be a mammal, typically a human.
Alternatively, the protein may be derived from a mammal, particularly a human, and is preferably a protein which mimics the structure of collagen or a collagen-derived protein or a plasma protein, such as the collagen-like segment of human serum component C1
q
.
Alternatively, the carrier may be a carbohydrate such as galactomannan or arabinogalactan or a lipopolysaccharide.
Further alternatively, the organic carrier may be a micelle, such as a liposome.
According to another aspect of the invention there is provided a diagnostic kit comprising a support containing a conjugate as described above immobilised thereon.
According to another aspect of the invention there is provided a pharmaceutical composition which comprises a therapeutic, prophylactic or tolerogenic amount of a conjugate as described above or a conjugate comprising any organic carrier and a purified lipid cell-wall component or analog or derivative thereof associated therewith or a biologically active purified lipid cell-wall component or analog or derivative thereof and a pharmaceutically acceptable or compatible pharmaceutical excipient, medium, carrier or adjuvant.
The organic carrier may be a protein including bovine serum albumin (BSA), gelatin, keyhole limpets haemocyanin and the CD1 molecule, or may be a carbohydrate or may be a micelle.
The pharmaceutical composition may also contain at least one immunomodulator. The immunomodulator may be a cytokine. The cytokine may be an interleukin, such as interleukin 4 (IL4), interleukin 10 (IL10) or interleukin 12 (IL12), or may be an interferon.
The suitable pharmaceutical carrier or adjuvant which may also be suitable for veterinary applications may be a solid, such as polymer dust, a liquid, such as an oil, typically Marcol 52, or a water-in-oil emulsion, typically Freund's Incomplete Adjuvant (FIA), or a solution, typically a saline solution or PBS, in which case the composition may be in the form of a suspension or a vapourised liquid, typically a neubulisable physiological saline solution, or a gas, or a transdermal delivery system.
The composition may comprise a therapeutic, prophylactic or tolerogenic amount of the purified lipid cell-wall component.
The pharmaceutical composition may comprise about 5 &mgr;g or less, typically 1 &mgr;g, of the purified lipid cell-wall component per ml of the composition.
A unit dose of the pharmaceutical composition for administration to a human subject preferably comprises from about 5 to 10 mg of the purified lipid cell-wall component.
According to another aspect of the invention there is provided a vaccine containing a purified lipid cell-wall component or analog or derivative thereof or a conjugate or a pharmaceutical composition as described above or a conjugate comprising any organic carrier and a purified lipid cell-wall component associated therewith for use in preventing an immune disorder or an inflammatory condition in a subject.
According to another aspect of the invention there is provided a vaccine containing a purified lipid cell-wall component or analog or derivative thereof or a conjugate or a pharmaceutical composition as described above or a conjugate comprising any organic carrier, except bovine serum albumin (BSA) and a purified lipid cell-wall component associated therewith, for use in preventing a microbial infection in a subject.
The organic carrier may be a protein including bovine serum albumin (BSA), gelatin, keyhole limpets haemocyanin and the CD1 molecule, or may be a carbohydrate or may be a micelle.
According to another aspect of the invention there is provided an isolated antibody which is capable of forming, separately, an antigen/antibody complex with any two or more of the following antigens: a purified lipid cell-wall component derived from a microorganism: a protein derived from a bacterial species or from a mammal; a conjugate as described above; and a conjugate comprising any organic carrier and a purified mycobacterial lipid cell-wall compon
Johannsen Elzbieta
Lenaerts Anne
Verschoor Jan Adrianus
Adcock Ingram Limited
Ladas & Parry
Weddington Kevin E.
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