Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution... – Containing or obtained from leguminosae
Reexamination Certificate
2001-08-31
2004-07-27
Tate, Christopher R. (Department: 1654)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
Containing or obtained from leguminosae
C514S825000, C514S885000, C514S903000
Reexamination Certificate
active
06767564
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to novel use of the Bowman-Birk protease inhibitor for the treatment of neuroinflammatory autoimmune diseases, such as Multiple Sclerosis and Guillain Barre Syndrome, and other inflammatory autoimmune diseases, such as rheumatoid arthritis.
BACKGROUND OF THE INVENTION
The Bowman-Birk protease inhibitor (BBI) was first described decades ago (Bowman et al.,
Arch. Biochem. Biophys.
16:109-113 (1948); Bowman et al.,
Proc. Soc. Exp. Biol. Med.
57:139-140 (1944)). The BBI protein consists of 71 amino acid residues and 7 disulfide bonds, and it has a molecular weight of 7975 daltons (Odani et al.,
J. Biochem.
74:697-715 (1973)). BBI contains two functional protease inhibitor domains of different specificities. It inhibits both trypsin and chymotrypsin-like proteases (Birk et al.,
J. Peptide Protein Res.
25:113-134 (1985)), wherein one domain inhibits chymotrypsin-like proteases, and the other inhibits trypsin-like proteases. Chymase and tryptase are serine proteases, which are stored in the cytosol, from which they may be released upon stimulation by potentially pro-inflammatory cells, such as mast cells or macrophages.
The potent ability of certain serine protease inhibitors, such as BBI, to prevent the malignant transformation of cells was discovered in the laboratory of Dr. Ann Kennedy more than two decades ago (e.g., U.S. Pat. Nos. 5,217,717 and 5,338,547; Kennedy et al.,
Nature
26:825-826 (1978); Yavelow et al,
Proc. Nat'l. Acad. Sci. USA
82:5395-5399 (1985); Kennedy, In
Protease
-
Inhibitors as Cancer Chemopreventive Agents
, Troll, W, Kennedy, A R (eds), New York, Plenum Press, 1993A, pp. 9-64; Kennedy,
Pharmacological Therapeutics
78:167-209 (1998)).
Bowman Birk Inhibitor Concentrate (BBIC) is a soybean-derived extract enriched in the protease inhibitor, BBI, developed by Dr. Kennedy as a cancer chemopreventative agent (Kennedy et al.,
Nutr. Cancer
19:281-302 (1993B); U.S. Pat. Nos. 4,793,996; 5,217,717 and 5,338,547). The use of BBIC is preferred over crude soybean extract because: a) a very large amount of crude soybean extract would be required to contain amounts of BBI equivalent to the proposed dose of BBIC (approximately 2 quarts of soybean milk or the equivalent amount of tofu); b) crude soybean extract may also contain components which actually counter some of the anticipated beneficial effects of BBI.
Because the anti-carcinogenic activity of BBI is associated with the chymotrypsin-inhibitory domain of BBI (Yavelow et al., 1985), BBIC is quantitated in chymotrypsin inhibitor (CI) units (one CI unit is defined as the amount required to inhibit one mg of chymotrypsin (Kennedy et al., 1993B). In April 1992, BBIC was granted Investigational New Drug status (IND #34671) from the Food and Drug Administration (FDA), and human trials to evaluate BBIC in several disease states are completed or in progress.
It is clear from animal studies that orally ingested BBI is absorbed and has systemic effects (reviewed in Kennedy, 1998). The structure of the BBI molecule is extremely stable (Birk, 1985; Birk,
Meth. Enzymol.
45:695-751 (1975)), such that it survives the digestive process as an intact protease inhibitor capable of inhibiting proteolytic activities. This contrasts with a number of other protease inhibitors which do not survive the digestive process (Kennedy, unpublished). Approximately 50% of the ingested BBI is absorbed into the bloodstream.
BBIC is reportedly a better inhibitor of human chymases than any physiologic protease inhibitor described to date. In a recently finished Phase IIa oral cancer chemoprevention trial in patients with pre-malignant lesions known as oral leukoplakia, daily doses of BBIC led to a significant decrease in lesion size in a dose-dependent manner (Meyskens et al.,
Proc. Amer. Assoc. Cancer Res.
40:Abstract #2855 (1999).
Significantly, no toxicity has been observed due to BBIC in any human trial (see Table in Detailed Description). No antibodies against BBIC have been found in the sera of any patients receiving BBIC orally (Maki et al.,
Nutr. Cancer
22:185-193 (1994); Kennedy, personal communication; U.S. Pat. No. 5,961,980).
Absorbed BBI is measurable using antibodies to reduced BBI, produced by injection into experimental animals and utilized in immunoassays (Wan at al., 1995). BBI has been assessed in the blood, tissue and urine of rodents and dogs after the ingestion of BBIC permitting pharmacokinetic studies, although it has not yet been feasible to measure BBI levels in the blood of humans after oral BBIC dosing. However, it has been found in the urine; starting within several hours after a single oral dose (Wan et at.,
Cancer Epidem. Biomarkers
&
Prevention
8:601-608 (1999)). Of note, studies in orally-dosed animals have shown that some BBI can be subsequently found in the CNS even when the blood-brain barrier is intact (Kennedy, A R, personal communication).
BBIC has also proven in many instances to be an effective anti-inflammatory agent. BBIC has been demonstrated to have a suppressive effect on inflammation occurring in carcinogen-treated rodents rodents, as measured by the level of inflammatory infiltrates or lymphoid aggregates, in organs such as the colon and esophagus. For example, in the treatment of ulcerative colitis, an inflammatory bowel disease (Ware et al.,
Digestive Diseases and Sciences
44:896-90 (1999)), inflammation was significantly reduced following treatment with BBIC. Moreover, the chemical induction of ulcerative colitis in rats resulted in the induction of many proteolytic activities in the lesioned, inflamed tissues, on which BBI/BBIC reportedly showed a highly significant inhibitory effect on essentially all of the induced proteolytic activities (Hawkins et al.,
Digestive Diseases and Sciences
42:1969-1980 (1996)). In addition, BBI/BBIC treatment resulted in a suppression of cancer development and a reduction in the levels of inflammation, as measured by the level of inflammatory infiltrates or lymphoid aggregates in the colon (Kennedy et al., 1993A).
Several possible mechanisms by which BBIC may cause these effects have been proposed. First, it has been suggested that BBIC interferes with the inflammatory response by reducing the production of oxygen radicals in in polymorphonuclear leukocytes. Second, BBIC reportedly decreases interleukin-1 (IL-1) release, which is a well known, pro-inflammatory cytokine, participating in a wide variety of immune and inflammatory reactions. Third, BBIC has been shown to have the ability to inhibit the malignant transformation of cells; it has been hypothesized that BBI may inhibit cell transformation by affecting the function of certain oncogenes/proto-oncogenes (e.g., c-myc and c-fos). Nevertheless, little is known yet about either the cellular or molecular mechanisms by which BBIC can modulate or ameliorate autoimmune diseases.
BBI has been shown to efficiently inhibit several identified proteases released from human inflammation-mediating cells. These include human leukocyte elastase Tikhonova et al.,
Biochemistry
(Moscow) 59:1295-1299 (1994); Larionova et al.,
Biochemistry
(Moscow) 58:1437-44 (1993)) and human cathepsin G (Larionova et al., 1993; Gladysheva et al.,
Biochemistry
(Moscow) 59(4):513-518 (1994)), which can efficiently destroy matrix molecules and severely damage tissues.
It is also known that BBI, as well an several other inhibitors of chymotrypsin proteolytic activity, have the ability to prevent the induction of superoxide anion radicals and hydrogen peroxide from stimulated human polymorphonuclear leukocytes and macrophage-like cells (Frenkel et al.,
Carcinogenesis
8:1207-1212 (1987): Ware et al.,
Nutr. Canc.
33:174-177 (1999)). Proteases and free radicals produced by macrophages are closely associated with the production of inflammation. For example, Multiple Sclerosis (MS) is characterized by inflammation and increased numbers of activated immunocytes and macrophage and T cell lineage (Hauser et. al., In
Harrison's Principles of Internal M
Kennedy Ann R.
Rostami Abdolmohamad
Dilworh Paxson LLP
Flood Michele C
McConathy Evelyn H.
Tate Christopher R.
The Trustees of the University of Pennsylvania
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