Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-10-21
2004-01-06
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C424S682000
Reexamination Certificate
active
06673782
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
BACKGROUND OF THE INVENTION
Systemic lupus erythematosis (SLE) is a systemic autoimmune disease with the potential to be directly involved in multiple organ systems. (See review by Kotzin, B. L.,
Cell
85:303-306, 1996.) The clinical manifestations of SLE include skin rash and joint pain, and severe and progressive kidney involvement. SLE patients typically present elevated serum levels of antibodies to nuclear constituents (i.e., antinuclear antibodies). In order to study the disease, workers have employed several animal models, including the F1 hybrid of New Zealand Black (NZB) and New Zealand White (NZW) mice, MRL mice homozygous for the lymphoproliferation (lpr) gene and BXSB mice, which carry the disease accelerating Yaa gene on the Y chromosome.
Principal targets of the autoantibodies produced in SLE patients include protein-nucleic acid complexes, such as chromatin, the U1 and Sm small nuclear ribonucleoprotein (snRNP) particles and the Ro/SSA and La/SSB RNP complexes (Tan, 1989; Cotson and Odell, 1995). Autoantibodies to phospholipids and cell surface molecules are also detected.
A majority of patients with SLE have symptoms of kidney failure. Clinical presentations typically include asymptomatic hematuria or proteinuria, acute nephritic or nephrotic syndromes, rapidly progressive glomerulonephritis and chronic renal insufficiency. (See Austin and Balow,
Seminars in Nephrology
19(1):2-11, 1999.)
Current treatments have addressed lupus nephritis, although commonly used therapeutic regimes are potentially toxic and may be ineffective for some high risk patients. Typically, intensive immunosuppressive regimes are prescribed. For severe SLE, immunosuppressives such as chemotherapies and cyclosporin are used. Other treatments include treatment with corticosteroids and cytotoxic drugs. Alternative therapies include treatment with cyclophosphamide and prednisone. Side effects of long term use of prednisone include development of high blood pressure, diabetes and osteoporosis.
Currently, many pharmaceutical companies are searching for alternative therapies. La Jolla Pharmaceutical Company (La Jolla, Calif.) is conducting phase II/III trials of LJP394 Toleragen, designed to target B cells that display anti-double stranded DNA antibodies that are implicated in kidney damage. Genelabs Technologies, Inc. is conducting a phase III trial of DHEA, a naturally occurring androgen, with the goal of overall disease reduction. Other drug therapies include IDEC-131, a humanized monoclonal antibody that targets CD40 on helper T cells (Idec Pharmaceuticals Corp., San Diego, Calif.) and a 5G1.1 C5 complement inhibitor (Alexion Pharmaceuticals, New Haven, Conn.).
Lemire, et al.,
Autoimmunity
12(2):143-148, 1992, describes the attenuation by 1,25-dihydroxyvitamin D
3
of some symptoms of experimental murine lupus in MRL/I mice.
1,25(OH)
2
D
3
and Analogs
The 1&agr;-hydroxylated metabolites of vitamin D—most importantly 1&agr;,25-dihydroxyvitamin D
3
and 1&agr;,25-dihydroxyvitamin D
2
—are known as highly potent regulators of calcium homeostasis in animals and humans. More recently, their activity in cellular differentiation has also been established. As a consequence, many structural analogs of these metabolites, such as compounds with different side-chain structures, different hydroxylation patterns, or different stereochemistry, have been prepared and tested. Important examples of such analogs are 1&agr;-hydroxyvitamin D
3
, 1&agr;-hydroxyvitamin D
2
, various side-chain fluorinated derivatives of 1&agr;,25-dihydroxyvitamin D
3
, and side-chain homologated analogs. Several of these known compounds exhibit highly potent activity in vivo or in vitro, and possess advantageous activity profiles and thus are in use, or have been proposed for use, in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, multiple sclerosis, arthritis and certain malignancies.
1,25-Dihydroxyvitamin D
3
as an Immunomodulator
The first indication that vitamin D might modulate immunity was the discovery that peripheral blood monocytes and activated T lymphocytes have 1,25-dihydroxyvitamin D
3
receptors (reviewed in Manolagas, S. C., et al.,
Mol. and Cell. Endocrin.
43:113-122, 1985). Despite many investigations, 1,25-dihydroxyvitamin D
3
immunomodulatory activity remains largely undefined and often controversial (reviewed in Manolagas, S. C., et al., supra, 1985; Rigby, W. F. C.,
Today
9:54-57, 1988; and Lemire, J. M., et al.,
J. Nutr.
125:1704S-1708S, 1995).
The action of 1,25-dihydroxyvitamin D
3
on human peripheral blood mononuclear cells (PBMC) has been studied extensively in vitro. These in vitro experiments showed that the hormone inhibited mitogen-stimulated proliferation of the PBMC (Lemire, J. M., et al.,
J. Clin. Invest.
74:657-661, 1984; Rigby, W. F. C., et al.,
J. Clin. Invest.
74:1451-1455, 1984) by reducing IL-2 production (Lemire, J. M., et al.,
J. Immunol.
134:3032, 1985; Iho, S., et al.,
Immunol. Let.
11:331-336, 1985; Manolagas, S. C., et al.,
J. Clin. Endocrinol. Met.
63:394, 1986) at the level of gene transcription (Alroy, I., et al.,
Mol. Cell. Biol.
15:5789-5799, 1995). In contrast, Bhalla, et al. (Bhalla, A. K., et al.,
J. Immunol.
133:1748-54, 1984) reported that the hormone did not inhibit mitogen-stimulated mouse spleen and thymus cell proliferation, although it did inhibit antigen-stimulated proliferation of these cells. Lacey, et al. (Lacey, D. L., et al.,
J. Immunol.
138:1680-1686, 1987) reported that the hormone actually stimulated mitogen-induced proliferation of cloned mouse T-cells. No studies have directly addressed the action of the hormone on T lymphocyte differentiation and function in vivo.
Disparate results have been reported for T lymphocyte IFN-y synthesis in vitro. Rigby, et al. (Rigby, W. F. C., et al.,
J. Clin. Invest.
79:1659-1664, 1987) and Reichel, et al. (Reichel, H., et al.,
Proc. Natl. Acad. Sci. USA
84:3387-3389, 1987) showed that 1,25-dihydroxyvitamin D
3
decreased IFN-&ggr; synthesis in mitogen-stimulated PBMC. However, Muller, et al. (Muller, K., et al.,
Immunol. Let.
35:177-182, 1993) reported that the hormone had no effect on IFN-&ggr; synthesis in human T-cell lines. The hormone inhibited cytotoxic T lymphocyte development but not cytotoxic function (Merino, F., et al.,
Cell. Immunol.
118:328-336, 1989).
There is controversy about 1,25-dihydroxyvitamin D
3
action on monocyte/macrophage cells in vitro. 1,25-Dihydroxyvitamin D
3
enhanced a myeloid leukemia cell's differentiation to the macrophage phenotype (Manolagas, S. C., et al., supra, 1985). It also increased monocyte/macrophage production of M-CSF, TNF-&agr;, and prostaglandin E2, but decreased IL-12 synthesis (Lemire, J. M., et al.,
FASEB J.
8:A745 (abs), 1994). The hormone decreased macrophage costimulatory function for T-cell proliferation (Rigby, W. F. C. and M. G. Waugh,
Arthritis Rheum.
35:110-119, 1992). Disparate results have been reported for 1,25-dihydroxyvitamin D
3
effects on IL-1 synthesis in vitro. The hormone decreased IL-1 synthesis in some reports (Iho, S., et al., supra, 1985; Tsoukas, C. S., et al.,
J. Clin. Endocrinol. Metab.
69:127-133, 1989) and increased IL-1 synthesis in other reports (Amento, E. P.,
J. Clin. Invest.
73:731-739, 1987; Bhalla, A. K., et al.,
Immunol.
72:61-64, 1991; Fagan, D. L., et al.,
Mol. Endocrinol.
5:179-186, 1991). Likewise, some investigators reported that 1,25-dihydroxyvitamin D
3
enhanced class II protein expression in vitro (Morel, P. A., et al.,
J. Immunol.
136:2181-2186, 1986) but others reported that it decreased class II protein expression (Amento, E. P., supra, 1987; Carrington, M. N., et al.,
J. Immunol.
140:4013-4018, 1988; Rigby, W. F. C., et al.,
Blood
76:189-197, 1990). Together these findings provide no clear and consistent view of how 1,25-dihydroxyvitamin D
3
might modify macrophage function. No studies have directly addressed the action of the ho
Cantorna Margherita T.
DeLuca Hector F.
Humpal-Winter Jean
Fay Zohreh
Quarles & Brady LLP
Wisconsin Alumni Research Foundation
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