Peptides which mimic candida carbohydrate epitopes and their...

Details Peptides which mimic candida carbohydrate epitopes and their... Peptides which mimic candida carbohydrate epitopes and their...

1998-05-13

2001-10-30

Duffy, Patricia A. (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Amino acid sequence disclosed in whole or in part; or...

C424S184100, C424S274100, C514S002600, C514S015800, C530S300000, C530S328000

Reexamination Certificate

active

06309642

ABSTRACT:

TECHNICAL FIELD
The present invention relates to peptides which mimic carbohydrate epitopes (mimotopes) of Candida and to a vaccine comprising the peptide or polynucleotides encoding the peptide mimotopes or antibodies to the peptides and a method for the treatment of disseminated candidiasis due to infection by
Candida albicans.
BACKGROUND OF THE INVENTION
Candida albicans
is a fungus responsible for various forms of candidiasis, a condition which may be found in normal and immunocompromised patients, such as those with acquired immune deficiency syndrome. Humans and mice who are neutropenic are especially at risk of developing disseminated candidiasis (Denning, D. W., et al. 1992. Antifungal prophylaxis during neutropenia or allogeneic bone marrow transplantation: what is the state of the art? Chemotherapy 38(suppl 1):43-49; Matsumoto, M. S., et al. 1991. Effect of combination therapy with recombinant human granulocyte colony-stimulating factor (rG-CSF) and antibiotics in neutropenic mice unresponsive to antibiotics alone. J. Antimicrob. Chemother. 28:447-453; Meunier, F. 1987. Prevention of mycoses in immunocompromised patients. Rev. Infect. Dis. 9:408-416; Meunier, F., et al. 1992. Candidemia in immunocompromised patients. Clin. Infect. Dis. 14 (Suppl 1):S120-S125; and Van't Wout, J. W. et al. 1989. Comparison of the efficacies of amphotericin B, Fluconazole, and Itraconazole against a systemic
Candida albicans
infection in normal and neutropenic mice. Antimicrob. Agents Chemother. 33: 147-151).
Several attempts have been made in the prior art to achieve immunostimulating compounds for the treatment of candidiasis as evidenced below.
U.S. Pat. No. 5,288,639 to Bernie et al. discloses the use of antibodies specific for stress proteins of
C. albicans
for the treatment of systemic candidiasis. Bernie et al. isolated a 47 kilo-dalton immunodominant antigen from
C. albicans
and found that serum from patients with systemic candidiasis reacts with the antigen. Monoclonal antibodies raised against the fungal stress proteins produced a 33% survival at 24 hours in animals challenged with a lethal dose of the
C. albicans.
U.S. Pat. No. 4,397,838 to d'Hinterland discloses preparations of purified proteoglycans extracted from bacterial membranes. The proteoglycans serve as immunoadjuvants and have an immunostimulating activity-without being immunogenic themselves. They are useful in serving as adjuvants with ribosomal vaccines such as a vaccine containing the ribosomes of
C. albicans.
U.S. Pat. No. 4,310,514 to Durette et al. discloses immunologically active dipeptidyl 5-O,6-O-acyl-2-amino-2-deoxy-D-glucofuranose derivatives. The compounds are used to delay the release of an antigen and stimulate the immune response of the host in conjunction with a vaccine. Compounds of Durette provide non-specific host protection against infectious organisms such as
C. albicans.
U.S. Pat. No. 4,315,913 to Durette discloses immunologically active dipeptidyl 2-amino-1,2-dideoxy-D-glucose derivatives. These derivatives are also useful as immunological adjuvants and themselves provide non-specific host protection against
C. albicans.
U.S. Pat. No. 4,368,910 to Shen et al. is directed to immunologically active dipeptidyl 4-O-6-O-acyl-2-amino-2-deoxy-D-glucose derivatives. These derivatives are indicated to be useful as immunogenic agents and vaccines and by themselves provide non-specific host protection against infectious organisms such as
C. albicans.
U.S. Pat. No. 4,323,560 to Baschang et al. is directed to phosphorylmuramyl peptides. The peptides are used to stimulate immunity. The compounds of Baschang et al. have been found to be inhibitive to infections caused by fungi such as
C. albicans.
U.S. Pat. No. 5,032,404 to Lopez-Berestein et al. disclose a liposomal agent for treating disseminated fungal infection in an animal. Because of the nature of polysaccharide fungal cell walls, it is expected that all medically important fungi activate complement. The patent indicated that there is a positive correlation between animals deficient in late-acting complement components and increased susceptibility to fungi such as
C. albicans.
The patent indicates that disseminated. fungal infection can be treated with liposomal agent comprised of lipids, a polyene macrolide anti-fungal compound and cholesterol. Lipids can include phosphatidyl choline. Liposomes incorporate an effective amount of a polyene macrolide anti-fungal compound such as hamycins or lucensomycin, filipin, lagosin and natamycin.
U.S. Pat. No. 4,678,748 to Sutka et al. discloses a process for the production of the immunobiological preparations applicable in the diagnosis, prevention and treatment of
Candida guilliermondii
infections. Strains of
C. guillienmondii
are killed and used to formulate a vaccine.
Early attempts at obtaining compounds which provide non-specific host protection against
C. albicans
are generally in the form of immuno adjuvants used in conjunction with vaccines.
More specific vaccine approaches include targeting aspects of
C. albicans
pathogenesis. An important aspect of pathogenesis is adherence of
C. albicans
to host tissue. Discussion below provides an understanding of adherence as it relates to pathogenesis of disseminated candidiasis.
C. albicans
is an organism that may show considerable variability of certain characteristics. Genetics studies show that the organism is diploid, but apparently without the ability to undergo meiosis, yet it has impressive genetic variability between and within strains (Scherer, S. et al. 1990. Genetics of
C. albicans.
Microbiol. Rev. 54:226-241). Chromosomal aberrations unpredictably occur (Rustchenko-Bulgac et al. 1990. Chromosomal rearrangements associated with morphological mutants provide a means for genetic variation of
C. albicans.
J. Bacteriol, 172:1276-1283), and may be related to high frequency phenotypic (colony) changes in some strains (Soll, D. R. 1992. High-frequency switching in
C. albicans.
Clin. Microbiol. Rev. 5:183-203). Perhaps related to the genetic instability are findings that strains of
C. albicans
variably express cell surface antigens (Cutler, J. E., et al. 1994. Antigenic variability of
C. albicans
cell surface. Curr. Top. Med. Mycol. 5:27-47, and Martinez, J. P., et al. 1990. Wall mannoproteins in cells from colonial phenotypic variants of
C. albicans.
J. Gen. Microbiol. 136:2421-2432). Some of these antigens include putative virulence factors such as adhesions and enzymes (Cutler, J. E. 1991. Putative virulence factors of
C. albicans.
Ann. Rev. Microbiol. 45:187-218).
Studies on adherence properties of
C. albicans
are important in gaining an understanding of
C. albicans
interactions with its host. The ability to bind to mucus and epithelial surfaces likely plays a critical role in maintaining
C. albicans
at these locations. The fungus also shows adherence specificities for selected populations of splenic and lymph node macrophages (Cutler, J. E., et al. 1990. Characteristics of
C. albicans
adherence to mouse tissue. Infect. Immun. 58:1902-1908; Han, Y., et al. 1993. Binding of
C. albicans
yeast cells to mouse popliteal lymph node tissue is mediated by macrophages. Infect. Immun. 61:3244-3249; and Kanbe, T., et al. 1992. Evidence that
C. albicans
binds via a unique adhesion system on phagocytic cells in the marginal zone of the mouse spleen. Infect. Immun. 60:1972-1978), and extracellular matrix proteins (ECM) and endothelial cells (Filler, S. G., et al. 1991.
C. albicans
stimulates endothelial cell eicosanoid production. J. Infect. Dis. 164:928-035; Klotz, S. A. 1992. Fungal adherence to the vascular compartment: A critical step in the pathogenesis of disseminated candidiasis. Clin. Infect. Dis. 14:340-347; Mayer, C. L., et al. 1992. Technical report:
C. albicans.
adherence to endothelial cells. Microvascular Res. 43:218-226; Rotrosen, D. et al. 1985. Adherence of Candida to cultured vascular endothelial cells: mechanisms of attachment and endothelial cell penetration. J. Infect.

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