Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific...
Reexamination Certificate
2001-03-16
2003-11-18
Ceperley, Mary E. (Department: 1641)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
C424S204100, C424S206100, C424S227100, C424S234100, C424S277100, C514S025000, C536S018200, C560S053000, C562S463000
Reexamination Certificate
active
06649172
ABSTRACT:
BACKGROUND OF THE INVENTION
The only vaccine adjuvant currently licensed for human use in the United States is alum, (see, Arnon and Regenmortel,
FASEB J.
1992, 6: 3265-3272) a group of aluminum salts which enhance humoral (antibody) immunity to vaccine antigens (Arnon and Regenmortel, 1992; Edelman,
Rev. Infect. Dis.
1980, 2: 370-383). The recognition that cell-mediated (thymus or T-cell) immune responses—particularly the induction of T-helper type 1 (Th-1) cells and cytotoxic T-lymphocytes (CTLs)—are crucial for generating protective immunity against many infectious agents has prompted efforts to discover new vaccine adjuvants which augment both antibody and T-cell responses (Arnon and Regenmortel, 1992).
The adjuvant properties of saponin were first recognized in France in the 1930's. (see, Bomford et al.,
Vaccine
1992, 10: 572-577). Two decades later the saponin from the bark of the
Quillaja saponaria
Molina tree found wide application in veterinary medicine, but the variability and toxicity of these crude preparations precluded their use in human vaccines. (see, Kensil et al.,
In Vaccine Design: The Subunit and Adjuvant Approach;
Powell, M. F., Newman, J. J., Eds.; Plenum Press: New York, 1995 pp. 525-541).
In the 1970's a partially purified saponin fraction known as Quil A was shown to give reduced local reactions and increased potency (see, Kensil et al., 1995). Further fractionation of Quil A, which consisted of at least 24 compounds by HPLC, demonstrated that the four most prevalent saponins, QS-7, QS-17, QS-18, and QS-21, were potent adjuvants (see, Kensil, C. R.
Crit Rev. Ther. Drug Carrier Syst.
1996, 13, 1-55; Kensil et al., 1995). QS-21 and QS-7 were the least toxic of these. Partly because of its reduced toxicity, highly purified state (though still a mixture of no less than four compounds), (see, Soltysik, S.; Bedore, D. A.; Kensil, C. R. Ann.
N.Y. Acad. Sci.
1993, 690: 392-395) and more complete structural characterization, QS-21 (3) was the first saponin selected to enter human clinical trials. (see, Kensil, 1996; Kensil et al., 1995).
QS-21 and other Quillaja saponins increase specific immune responses to both soluble T dependent and T-independent antigens, promoting an Ig subclass switch in B-cells from predominantly IgG1 or IgM to the IgG2a and IgG2b subclasses (Kensil et al., 1995). The IgG2a and IgG2b isotypes are thought to be involved in antibody dependent cellular cytotoxicity and complement fixation (Snapper and Finkelman,
In Fundamental Immunology,
4th ed.; Paul, W. E., Ed.: Lippincott-Raven: Philadelphia, Pa., 1999, pp. 831-861). These antibody isotypes also correlate with a Th-1 type response and the induction of IL-2 and IFN-&ggr;-cytokines which play a role in CTL differentiation and maturation (Constant and Bottomly,
Annu. Rev. Immunology
1997, 15: 297-322). As a result, QS-21 and other Quillaja saponins are potent inducers of class I MHC-restricted CD8+ CTLs to subunit antigens (Kensil, 1996; Kensil et al., 1995).
The mechanisms of saponin action have been investigated both by chemical modification of QS-21 and other saponins and by assessing the adjuvant activity of structurally diverse saponins (see, Bomford et al.,
Vaccine
1992, 10: 572-577; Soltysik et al.,
C. R. Vaccine
1995, 13: 1403-1410; Kensil et al.,
Adv. Exp. Med. Biol.
1996, 404: 165-172; Kensil et al.,
J. Dev. Biol. Stand.
1998, 92: 41-47). As the name suggests, saponins are surface-active adjuvants due to their amphipathic structure and ability to form micelles in solution. While micelle formation does not appear essential to saponin adjuvanticity, QS-21 may promote CD8+ CTL responses by associating with and disrupting the cell surface of antigen-presenting cells (APCs) and directing soluble antigen into the cytoplasm (Kensil, 1996). The importance of the complex fatty acid domain of QS-21 for CTL activity is not clear as hydrophilic saponins also induce cell-mediated responses (see, Kensil et al., 1998; So et al.,
Mol. Cells
1997, 7: 178-186).
An important structural feature for saponin adjuvanticity appears to be the formyl group at C-4 of
Blocking the aldehyde of QS-21 or reducing it to an alcohol abolishes adjuvant activity, (see, Soltysik et al., 1995) suggesting that Schiff base formation (the reversible reaction of an aldehyde with an amine to form an imine: RCHO+RNH
2
→RCH═NR) is important to saponin adjuvanticity. Since saponins are effective adjuvants with hydrophilic polysaccharides lacking amino groups, (Kensil, 1996), Schiff base formation with cells of the immune system is likely. Indeed, Schiff base formation is thought to play an important role in APC-T-cell interactions and appears to be a critical determinant of the immunopotentiating ability of the zenobiotic tucaresol and other amphipathic aldehydes (see, Rhodes,
Immunol. Today
1996, 17: 436-441; Hazen et al.,
J. Biol. Chem.
1997, 272: 16990-16998). Amphipathic aldehydes can substitute for the carbonyl groups constitutively expressed on APCs by forming a Schiff base with CD4+ T-cell surface amines and providing a costimulatory signal which leads to a Th-1 type profile of cytokine production and the enhancement of MHC class I-restricted CTL responses (Rhodes, 1996).
Potent, low-toxicity adjuvants which drive both effector arms of the immune system are needed to improve the safety and efficacy of existing vaccines and potentiate the weak immunogenicity of nascent synthetic vaccines. The present invention fulfills the aforementioned and other needs.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound represented by the Formula I:
In Formula I, the symbol R represents hydrogen or —C(O)H. The symbol R
1
represents a member selected from hydrogen, a substituted C
1-20
alkyl group, an unsubstituted C
1-20
alkyl group, a saccharyl group, and a group represented by the formula —C(O)—[C(R
3
)(R
4
)]
n
—COOH or —[C(R
3
)(R
4
)]
n
—COOH, wherein each R
3
and R
4
independently is a member selected from hydrogen, a substituted C
1-10
alkyl group, an unsubstituted C
1-10
alkyl group. The symbol n represents an integer from 1 to 5. The symbol R
2
represents a member selected from hydrogen, a substituted C
1-20
alkyl group, an unsubstituted C
1-20
alkyl group, and a group represented by the formula —(CH
2
)
m
CH(OH)(CH
2
)
p
OR
5
, wherein m and p are independently 1 or 2, and R
5
is a C
2-20
acyl group, or a group represented by the formula
wherein j is an integer from 1 to 5, and R
6
and R
7
are independently selected from the group of hydrogen, a substituted C
1-20
alkyl group, and an unsubstituted C
1-20
alkyl group; or a pharmacologically acceptable salt thereof.
In a second aspect, the present invention provides a liposome vesicle comprising a compound of Formula I.
In a third aspect, the present invention also provides a compound comprising an antigen covalently linked to a compound according to Formula I.
In a fourth aspect, the present invention also provides a vaccine composition comprising an antigen and a compound of Formula I.
In a fifth aspect, the present invention also provides an adjuvant composition for potentiating the immunogenicity of an antigen, including a suspension of water or an aqueous solution. The suspension or solution includes a compound according to Formula I.
The present invention also provides a method for inducing or enhancing immunogenicity of an antigen in a mammal. The method includes administering to the mammal a vaccine composition that includes the antigen and a vaccine adjuvant composition that includes an effective immunopotentiatory amount of a compound according to Formula I.
In a seventh aspect, the present invention also provides a method for treating or preventing a disease in a mammal. The method includes administering to the mammal a vaccine composition. The vaccine composition includes an antigen and an effective immunopotentiatory amount of a compound according to Formula I.
The present invention also provides methods for preparing adj
Ceperley Mary E.
Corixa Corporation
Townsend and Townsend / and Crew LLP
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