Adjuvant comprising a lipopolysaccharide antagonist

Details Adjuvant comprising a lipopolysaccharide antagonist Adjuvant comprising a lipopolysaccharide antagonist

2003-02-27

2004-07-06

Park, Hankyel T. (Department: 1648)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

C435S007200, C435S810000, C424S184100, C424S234100

Reexamination Certificate

active

06759241

ABSTRACT:

1. FIELD OF THE INVENTION
The invention provides a novel vaccine adjuvant comprising lipopolysaccharide (LPS) antagonist, and use of the same in vaccine preparations and methods of vaccinating a subject comprising a vaccine antigen and a pharmaceutically active amount of an LPS antagonist.
2. BACKGROUND OF THE INVENTION
2.1 General Properties of Adjuvants
An adjuvant is a compound that, when combined with a vaccine antigen, increases the immune response to the vaccine antigen over that induced by the vaccine antigen alone. Strategies that promote antigen immunogenicity include those that render vaccine antigens particulate, polymerize vaccine antigens, emulsify vaccine antigens, encapsulate vaccine antigens, increase host innate cytokine responses, or target vaccine antigens to antigen presenting cells (Nossal, 1999, In: Fundamental Immunology. Paul (Ed.), Lippincott-Raven Publishers, Philadelphia, Pa.; Vogel and Powell, 1995, In: Vaccine Design. The Subunit and Adjuvant Approach. Powell and Newman (Eds.), Plenum Press, NY, N.Y. p. 141). Because of the essential role adjuvants play in improving the immunogenicity of vaccine antigens, the use of adjuvants in the formulation of vaccines has been virtually ubiquitous (Nossal, 1999, supra; Vogel and Powell, 1995, supra; see also PCT publication WO 97/18837, the teachings of which are incorporated herein by reference).
A compendium of adjuvants with know immunomodulatory properties is available (Vogel and Powell, 1995, supra). Examples of well-known adjuvants include Freund's adjuvant (Vogel and Powell, 1995, supra), MF59 (Vogel and Powell, 1995, supra; Ott, et al., 1995, In; Vaccine Design. The subunit and adjuvant approach. Powell and Newman (Eds.), Plenum Press, NY, N.Y. p.277; Traquina, et al., 1996, J. Infect. Dis., 174:1168; Ott, et al., 1995, Pharm. Biotechnol., 6:277), SAF-1 (Vogel and Powell, 1995, supra), polylactide co-glycolide encapsulation (PLG; (Vogel and Powell, 1995, supra; Eldridge, et al., 1991, Infect. Immun., 59:2978; Eldridge, et al., 1993, Semin. Hematol., 30:16; Vordermeier, et al., 1995, Vaccine 13:1576; Ugozzoli, et al., 1998, Immunol., 93:563), aluminium hydroxide/phosphate (“Alum”; (Vogel and Powell, 1995, supra; Edelman, 1980, Rev. Infect. Dis., 2:370; Seppala and Makela, 1984, Immunol., 53:827; Shirodkar, et al., 1990, Pharm Res., 7:1282; Weissburg, et al., 1995, Pharm. Res., 12:1439), and immune-stimulating complexes (“ISCOMs”; Vogel and Powell, 1995, supra; Rimmelzwaan and Osterhaus, 1995, In: Vaccine Design. The Subunit and Adjuvant Approach. Powell and Newman (Eds.), Plenum Press, NY, N.Y. p.543; Sjolander, et al., 1998, J. Leukoc. Biol., 64:713; Morein, 1990, Vet. Microbiol., 23:79; Lovgren and Morein, 1991, Molec. Immunol., 28:285).
A more recent adjuvant strategy has been to use purified recombinant cytokines as adjuvants (Vogel and Powell, 1995, supra). Cytokines that have been employed in this fashion include IL-1a, TNFa, IL-2, IL4, IL-6, IL-12, interferon-gamma (IFN-&ggr;), and granulocyte monocyte colony stimulating factor (GM-CSF; Nossal, 1999, supra; Vogel and Powell, 1995, supra; Nash, et al., 1993, Immunol. Cell. Biol., 71:367; Pardoll, 1995, Annu. Rev. Immunol., 13:399; Kurane, et al., 1997, Ann. Surg. Oncol., 4:579; Tagliabue and Boraschi, 1993, Vaccine, 11:594; Lofthouse, et al., 1995, Vaccine, 13:1131; Pasquini, et al., 1997, Immunol. Cell. Biol., 75:397; Jankovic, et al., 1997, J. Immunol., 159:2409).
The advent of nucleic acid vaccines has enabled new avenues in the field of adjuvant development. This includes the use of nucleic acid vaccines that encode cytokines, such as IL-4, IFN-&ggr; and GM-CSF, in addition to the vaccine antigen (Pasquini, et al., 1997, supra) and nucleic acid vaccines that encode co-stimulatory molecules such as CD80 (also known as B7.1), in addition to the vaccine antigen (Pasquini, et al., 1997, supra).
Although there is no single mechanism of adjuvant action, an essential characteristic of adjuvants is their ability to significantly increase the level of immunity to a vaccine antigen over the level of immunity induced by the vaccine antigen alone (Nossal, 1999, supra; Vogel and Powell, 1995, supra). In this regard, some adjuvants are more effective at augmenting humoral immune responses; other adjuvants are more effective at increasing cell-mediated immune responses (Vogel and Powell, 1995, supra); and yet another group of adjuvants increase both humoral and cell-mediated immune responses against vaccine antigens (Vogel and Powell, 1995, supra).
Several adjuvants are derived from bacterial products. Bacteria are composed of a diverse array of biologically active components that have proven adjuvant activity, including porins, cholera toxin (also called “C”), heat-labile toxin of enterotoxigenic
E. coli
(also called LT), muramyl dipeptide, lipoarabinomannans (“LAM”), lipid A, and monophosphoryl-lipid A (Nossal, 1999, supra; Vogel and Powell, 1995, supra; Lidgate and Byars, 1995, In: Vaccine Design. The Subunit and Adjuvant Approach. Powell and Newman (Eds.), Plenum Press, NY, N.Y. p.313; Ulrich and Myers, 1995, In: Vaccine Design. The Subunit and Adjuvant Approach. Powell and Newman (Eds.), Plenum Press, NY, N.Y. p.495). In addition, unmethylated CpG DNA sequences, which are expressed by bacteria or made synthetically, have been shown to possess potent immunostimulatory properties (Davis, et al., 1998, J. Immunol., 160:870; Klinman, 1998, Antisense Nucleic Acid Drug Dev., 8:181; Liu, et al., 1998, Blood, 92:3730; Wloch, et al., 1998, Hum. Gene. Therap., 9:1439; Brazolot-Milla, et al., 1998, Proc. Natl. Acad. Sci. USA, 95:15553; Moldoveanu, et al., 1998, Vaccine, 16:1216). Inclusion of such sequences in nucleic acid vaccines is thought to play a key role in the immunogenicity of DNA vaccines (Davis, et al., 1998, supra; Klinman, 1998, supra; Liu, et al., 1998, supra; Wloch, et al., 1998, supra; Brazolot Milla, et al., 1998, supra; Moldoveanu, et al., 1998, supra).
2.2 Bacterial LPS and Lipid A
LPS (lipopolysaccharide), also referred to as “endotoxin”, is the major surface component of gram negative bacteria. Under normal conditions, LPS is inserted in the outer surface of the outer membrane of gram negative bacteria (Schnaitman and Klena, 1993, Microbiol. Rev., 57:655; Makela and Stocker, 1984, In: Handbook of Endotoxin volume 1, Elsevier Biomedical Press, Amsterdam, Rietschel (Ed.), pp. 59-137). Complete or “smooth” LPS is composed of three main domains called lipid A, the O-antigen (also called the O-polysaccharide) and the core region, which creates an oligosaccharide link between lipid A and the O antigen (Schnaitman and Klena, 1993, supra; and Makela and Stocker, 1984, supra). The O-antigen is composed of oligosaccharide repeat units. The structure and number of these repeats varies depending on the bacterial species and growth conditions, typically ranging from one to fifty repeats (Schnaitman and KIena, 1993, supra; and Makela and Stocker, 1984, supra). Some bacterial generi, such as Neisseria spp., produce LPS that has low numbers of O-antigen repeats and therefore is referred to as lipooligosaccharide (LOS) simply to reflect this fact (Schnaitman and Klena, 1993, supra; and Makela and Stocker, 1984, supra).
The biologically active component of LPS is lipid A (Rietschel, et al., 1994, FASEB J., 8:217; Verma, et al., 1992, Infect. Immun., 60:2438; Alving, 1991, J. Immunol. Meth., 140:1; Alving and Richards, 1990, Immunol. Lett., 25:275; Richard, et al., 1988, Infect. Immun., 56:682. Activity analysis of lipid A biosynthesis precursors or synthetic intermediates showed that various elements of lipid A are essential for pyrogenicity (Rietschel, et al., 1994, supra; Raetz, et al., 1985, J Biol. Chem., 260:16080). Lipid X and lipid IVa are completely non pyrogenic precursor forms of lipid A (Wang, et al., 1991, Infect. Immun., 59:4655; Ulmer, et al., 1992, Infect. Immun., 60:145; Kovach, et al., 1990, J. Exp. Med., 172:77).
Lipid X is a monosaccharide precursor of lipid A (Rietschel, et al., 1994, supra). Lipid IVa, a tetraacyl precursor of lipid

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