Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-06-03
2002-04-09
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C514S054000, C514S885000, C514S944000, C514S951000, C514S959000, C514S962000, C536S123100, C536S124000
Reexamination Certificate
active
06369216
ABSTRACT:
BACKGROUND OF THE INVENTION
Underivatized, aqueous soluble &bgr;(1,3)-glucan (also known as PGG-glucan, triple helix-glucan (TH-glucan) or Betafectin®) is a novel and unique soluble &bgr;-glucan manufactured through a proprietary process. The biological activity of this molecule is clearly distinguishable from particulate or other soluble &bgr;-glucans. Numerous laboratories have reported direct induction of arachidonic acid metabolites (Czop et al.,
J. Immunol.
141(9):3170-3176 (1988)), cytokines (Abel and Czop,
Intl. J. Immunopharmacol.
14(8):1363-1373 (1992); Doita et al.,
J. Leuk. Biol.
14(2):173-183 (1991)) and oxidative burst (Cain et al.,
Complement
4:75-86 (1987); Gallin et al.,
Int. J. Immunopharmacol.
14(2):173-183 (1992)) by both particulate and soluble forms of &bgr;-glucans. In contrast, underivatized, aqueous soluble &bgr;(1,3)-glucan does not directly activate leukocyte functions such as oxidative burst activity (Mackin et al.,
FASEB J.
8:A216 (1994)), cytokine secretion (Putsiaka et al.,
Blood
82:3695-3700 (1993)) or proliferation (Wakshull et al.,
J. Cell. Biochem. suppl.
18A:22 (1994)). Instead, underivatized, aqueous soluble &bgr;(1,3)-glucan primes cells for activation by secondary stimuli (Mackin et al. (1994); Brunke-Reese and Mackin,
FASEB J.
8:A488 (1994); and Wakshull et al. (1994)).
The biological activity of &bgr;-glucans is mediated through specific receptors located on target cells. Several groups of investigators have described receptors which bind to and mediate phagocytosis of particulate &bgr;-glucan preparations (e.g., zymosan-like particles; Goldman (
Immunology
63(2):319-324 (1988);
Exp. Cell. Res.
174(2):481-490 (1988); Engstad and Robertsen,
Dev. Comp. Immunol.
18(5):397-408 (1994); Muller et al.,
Res. Immunol.
145:267-275 (1994)); Czop,
Advances in Immunol.
38:361,398 (1986)); and have partially characterized these receptors (Czop and Kay,
J. Exp. Med.
173:1511-1520 (1991); Szabo et al.,
J. Biol. Chem.
270:2145-2151 (1995)). The leukocyte complement receptor 3 (CR3, also known as MAC 1 or CD11b/CD18) has been reported to bind both particulate and some soluble &bgr;-glucans, as well as other polysaccharides (Thornton et al.,
J. Immunol.
156:1235-1246 (1996)). A soluble aminated &bgr;-glucan preparation has been shown to bind to murine peritoneal macrophages (Konopski et al.,
Biochim. Biophys. Acta
1221:61-65 (1994)), and a phosphorylated &bgr;-glucan derivative has been reported to bind to monocyte cell lines (Muller et al.,
J. Immunol.
156:3418-3425 (1996)).
SUMMARY OF THE INVENTION
The present invention relates to &bgr;-glucan compositions comprising &bgr;-glucan molecules having an average molecular weight of at least 1,000,000 daltons, as determined by multi-angle laser light scattering (MALLS), and referred to herein as very high molecular weight glucans (VHMW-glucans). The VHMW-glucans are soluble in aqueous solutions and are underivatized, i.e., the VHMW-glucans have not been substantially modified by substitution with functional groups. The VHMW-glucans of the invention have a high affinity for the TH-glucan receptor on human monocytes, as well as a novel receptor located primarily on rat NR8383 macrophages, particularly alveolar macrophages. The &bgr;-glucan compositions of the present invention have been shown to enhance host immune defense mechanisms to infection, but do not induce an inflammatory response. Specifically, VHMW-glucans retain a specific subset of immunological properties common to &bgr;-glucans but uniquely do not induce the production of detrimental pro-inflammatory cytokines, such as TNF-&agr;, IL-1&bgr; and IL-6. Further, VHMW-glucans have been shown to accelerate bacterial clearance and increase platelet counts in both rat and mice infection models.
The VHMW-glucans can be formulated into a composition appropriate for parenteral (e.g., intravenous, interparenteral, subcutaneous, intramuscular), topical, oral or internasal administration to humans and animals as an anti-infective to combat infection associated with burns, surgery, chemotherapy, bone marrow disorders and other conditions in which the immune system may be compromised. The VHMW-glucan compositions of the present invention can be used in therapeutic and/or prophylatic treatment regimens of humans and animals to enhance their immune response, without stimulating the production of certain biochemical mediators (e.g., IL-1&bgr;, TNF-&agr; and IL-6) that can cause detrimental side effects, such as fever and inflammation. The VHMW-glucan compositions can be used for therapeutic or prophylactic application, such as immunosuppression, hematopoiesis, wound healing, prevention and treatment of infectious disease, platelet production, peripheral blood precursor cell mobilization, and induction and enhancement of myelopoeisis and thrombopoeisis.
REFERENCES:
patent: 3943247 (1976-03-01), Komatsu et al.
patent: 4138479 (1979-02-01), Truscheit et al.
patent: 4237266 (1980-12-01), Sugiura et al.
patent: 4707471 (1987-11-01), Larm et al.
patent: 4739046 (1988-04-01), DiLuzio et al.
patent: 4761402 (1988-08-01), Williams et al.
patent: 4810646 (1989-03-01), Jamas et al.
patent: 4946450 (1990-08-01), Erwin
patent: 4975421 (1990-12-01), Williams et al.
patent: 4992540 (1991-02-01), Jamas et al.
patent: 5032401 (1991-07-01), Jamas et al.
patent: 5057503 (1991-10-01), Czop et al.
patent: 5320849 (1994-06-01), Hagiwara et al.
patent: 5322841 (1994-06-01), Jamas et al.
patent: 5401647 (1995-03-01), Tanaka et al.
patent: 5474984 (1995-12-01), Tanaka et al.
patent: 5488040 (1996-01-01), Jamas et al.
patent: 5504079 (1996-04-01), Jamas et al.
patent: 5532223 (1996-07-01), Jamas et al.
patent: 5622939 (1997-04-01), Jamas et al.
patent: 5633369 (1997-05-01), James et al.
patent: 5663324 (1997-09-01), James et al.
patent: 5783569 (1998-07-01), Jamas et al.
patent: 5811542 (1998-09-01), James et al.
patent: 5817643 (1998-10-01), Jamas et al.
patent: 322393 (1989-06-01), None
patent: 0416343 (1991-03-01), None
patent: 0463540 (1992-01-01), None
patent: 2076418 (1981-12-01), None
patent: 55071701 (1980-08-01), None
patent: 56076401 (1981-09-01), None
patent: 59045301 (1984-06-01), None
patent: 59210901 (1995-04-01), None
patent: 91/03248 (1991-03-01), None
patent: 91/03495 (1991-03-01), None
patent: 92/13896 (1992-08-01), None
patent: 94/03498 (1994-02-01), None
patent: 94/03500 (1994-02-01), None
patent: 94/04163 (1994-03-01), None
Janusz et al., “Isolation of Soluble Yeast Beta-Glucans that Inhibit Human Monocyte Phagocytosis Mediated by Beta-Glucan Receptors”, Journal of Immunology, vol. 137, No. 10, Issued Nov. 15, 1986, pp. 3270-3276.*
Manners, D.J., et al., “The Structure of a &bgr;-(-3)-D-Glucan from Yeast Cell Walls,”Biochem. J. 135:19-30 (1973).
Fleet, G.H., et al., “Isolation and Composition of an Alkali-Soluble Glucan from the Cell Walls ofSaccharomyces cerevisiae,”J. Gen. Microbio. 94:180-192 (1976).
Miyazaki, T., et al., “Structural Examination of Antitumour, Water-Soluble Glucans fromGrifora umbellataby Use of Four Types of Glucanese,”Carbohydrate Research65:235-243 (1978).
Reiskind, J.B. and Mullins, J.T., “Molecular Architecture of the Hyphal Wall ofAchlya ambisexualisRaper. II. Ultrastructural Analyses and a Proposed Model,”Can. J. Microbiol. 27:1100-1105 (1981).
Latgé, J.P., et al., “Composition Chimique et Ultrastructure des Parois des Hyphaux et des Azygospores deConidiobolus obscurus,”Can. J. Microbiol. 30:1507-1421 (1984).
Sherwood, E.R., et al., “Soluble Glucan and Lymphokine-Activated Killer (LAK) Cells in the Therapy of Experimental Hepatic Metastases,”Chemical Abstracts108:179752v (1988).
Hara, C., et al., “A Branched (1-3)-&bgr;-D-Glucan from a Water Extract ofDictyophora indusiataFISCH,”Carb. Res. 145:237-246 (1986).
Goldman, R., “Induction of a &bgr;-1,3-D-Glucan Receptor in P388D1 Cells Treated with Retinoic Acid of 1,25-dihydroxyvitamin D3,”Immunology63:319-324 (1988).
Konopski, A., et al., “Phagocytosis of &bgr;-1,3-D-Glucan-Derivatized Microbeads by Mouse Peritoneal Macrophages Involves Three Different Recept
Easson, Jr. D. Davidson
Jamas Spiros
Ostroff Gary R.
Patchen Myra L.
Biopolymer Engineering Pharmaceutical, Inc.
Geist Gary
Hamilton Brook Smith & Reynolds P.C.
White Everett
LandOfFree
Very high molecular weight &bgr;-glucans does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Very high molecular weight &bgr;-glucans, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Very high molecular weight &bgr;-glucans will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2825115