Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-04-09
2002-12-10
Criares, Theodore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S013800, C514S613000, C514S617000
Reexamination Certificate
active
06492333
ABSTRACT:
TECHNICAL FIELD
The invention relates to compositions and methods for use in treating bone disease associated with myeloma. More specifically, the invention concerns the use of inhibitors of proteasomal and NF-&kgr;B activity for this purpose.
BACKGROUND ART
Multiple myeloma is the second most common hematologic malignancy producing some 15,000 new diagnosed cases each year in the United States with the number of existing myeloma patients numbering between 30,000 to 40,000 (Mundy et al.
Seminar Oncol
(1986) 3:291). Eighty percent of whom suffer from devastating osteolytic bone destruction caused by increases in osteoclast formation and activity (Mundy et al. (1986), supra). The associated bone destruction can cause severe bone pain, pathologic fractures, spinal cord compression, and life-threatening hypercalcemia. It has been reported that multiple myeloma cannot be cured by standard chemotherapy or stem cell transplantation (Attai et al.
Blood
(1996) 87(4):1495-1501).
Myeloma bone disease results in severe morbidity and potential mortality. Accordingly, the development of strategies and treatments that control the osteolytic bone destruction resulting in these patients has become of vital importance.
However, the pathologic mechanisms responsible for increased osteoclast activity in multiple myeloma patients are unknown. Further, the accompanying bone lesions that occur in the patients take on several pattern forms. Occasionally, patients develop discrete osteolytic lesions in association with solitary plasmacytomas. Other patients have diffuse osteopenia, which mimics the appearance of osteoporosis, and results from the diffuse dispersion of the myeloma cells throughout the axial skeleton. In most atients, there are multiple discrete lytic lesions occurring adjacent to nests of myeloma ells. Hypercalcemia occurs as a consequence of bone destruction in about one third of atients with advanced bone disease. Rarely do patients with myeloma fail to develop lytic lesions or bone loss, instead they have an increased new bone formation around myeloma cells. This rare situation is known as osteosclerotic myeloma.
Osteolytic bone lesions are the most common deleterious skeletal manifestation in patients with myeloma. Although the precise molecular mechanisms remain unclear, nevertheless observations over 15 years have revealed several facts. First, the mechanism by which bone is destroyed in myeloma occurs via the osteoclast, the normal bone-resorbing cell. Second, osteoclasts accumulate on bone-resorbing surfaces in myeloma adjacent to collections of myeloma cells. Thus, it appears that the mechanism by which osteoclasts are stimulated in myeloma is a local one. Third, it has been known for many years that cultures of human myeloma cells, in vitro, produce several osteoclast-activating factors, including lymphotoxin, interleukin-1 (IL-1), and interleukin-6 (IL-6). Fourth, hypercalcemia occurs in approximately one third of patients with myeloma at some point during the course of the disease. Hypercalcemia is always associated with markedly increased bone resorption, and frequently with the impairment in glomerular filtration. Fifth, the increase in osteoclastic bone resorption in myeloma is usually associated with a marked impairment in osteoblast function. Alkaline phosphatase activity in the serum is decreased or remains in the normal range, in contrast to patients with other types of osteolytic bone disease. Also, radionuclide scans do not show evidence of increased uptake, which indicates impaired osteoblast response to the increase in bone resorption.
Various mediators have been implicated in the stimulation of osteoclast activity in patients with multiple myeloma, including lymphotoxin (tumor necrosis factor-&bgr; (TNF&bgr;)), interleukin-1-beta (IL-1&bgr;), parathyroid hormone-related protein (PTHrP), and interleukin-6 (IL-6). However, reports of factors that are produced by myeloma cells have been wholly inconsistent. Some studies have been inconclusive due to the presence of other contaminating cell types including stromal cells and macrophages in the multiple myeloma cell population. IL-6 is a major myeloma growth factor that enhances the growth of several myeloma cell lines and those cells freshly isolated from myeloma patients (Bataille et al.
J Clin Invest
(1989) 84:2008). IL-6 production can be detected in about 40% of freshly isolated myeloma cells by PCR, but only 1 in 150 patients studied show detectable IL-6 production by immunocytochemistry or ELISA assays (Epstein J.
Hematology/Oncology Clinics of North America
(1992) 6:249-256. The IL-6 receptors were only detected in 6 of 13 samples from patients with multiple myeloma (Bataille et al.
Hematology/Oncology Clinics of North America
(1992) 6:285-295). Furthermore, mature myeloma cells have been reported to have a minimal proliferative response to interleukin-6. Interleukin-11 (IL-11) has an IL-6-like activity on plasmacytomas, but to date no one has demonstrated that myeloma cells produce IL-11. Bataille and coworkers (Bataille et al.
Blood
(1995) 86(2):685-91) have shown that the perfusion of 5 patients with refractory myeloma with an antibody of IL-6 decreased the size of the myeloma cell burden in only 2 of these patients.
In addition to IL-6 and IL-1&bgr;, TNF&agr; and lymphotoxin have been implicated as mediators of bone destruction in multiple myeloma. IL-6 is an extremely potent bone-resorbing agent that induces hypercalcemia in animal models in the absence of renal failure (Boyce et al.
Endocrinology
(1989) 125:2780-2783). In contrast, hypercalcemia rarely occurs in myeloma patients without renal failure. More importantly, in highly purified myeloma cells, no IL-1&bgr; and only rare TNF&agr; production can be detected, suggesting that other contaminating cell types such as macrophages may be the source of the IL-1&bgr; and TNF&agr; (Epstein (1992), supra). Similarly, lymphotoxin is produced by most human myeloma cell lines (Bataille et al. (1995), supra) but does not appear to be produced by myeloma cells in vivo (Alsina et al.
Blood
(1996) 87(4):1495-1501). In addition to IL-1&bgr;, TNF&agr;, lymphotoxin and IL-6, myeloma cells produce a truncated form of M-CSF which is biologically active. However, M-CSF does not cause hypercalcemia or induce osteoclast formation by itself in human marrow cultures (MacDonald et al.
J Bone Miner Res
(1986) 1:227-233). Thus, the specific role played by many of these factors in osteolytic bone disease occurring in myeloma patients has not been definitively illustrated in vivo. Thus, the known cytokines do not entirely account for the bone resorption observed in these patients.
Furthermore, freshly isolated marrow supernatants from the affected bones in myeloma patients contain a bone-resorbing activity that comprises an unknown resorbing cytokine. These data suggest that myeloma cells produce factors in the marrow microenvironment that differ from those produced by the cells in vitro and that this factor(s) is not a cytokine previously known to be produced by myeloma cells.
NF-&kgr;B is a transcription factor which regulates the expression of the kappa light chain gene in murine B lymphocytes, but is now known to be expressed ubiquitously. A number of different NF-&kgr;B proteins have been identified and well-characterized (Siebenlist et al.
Annu Rev Cell Biol
(1994) 10:405-455; see also, Baeurele et al. Cell (1996) 87:13-20). NF-&kgr;B in its active state is a heterodimer, which consists usually of two subunits. The most common subunits are known as P65 and P50; another common subunit is P52. Different combinations of these subunits may be involved in the observation of different target genes. In unstimulated cells, NF-&kgr;B is both present in the cytoplasm and bound to other proteins known as IkB&agr; and IkB&bgr; and prevent it from entering the nucleus. Upon stimulation of cells, specific enzymes lead to the phosphorylation of IkB, which in turn leads to its rapid degradation in the proteasomes. Upon degradation of IkB, NF-&kgr;B is then available to
Criares Theodore J.
Morrison & Foerster / LLP
Osteoscreen Inc.
LandOfFree
Treatment of myeloma bone disease with proteasomal and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Treatment of myeloma bone disease with proteasomal and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Treatment of myeloma bone disease with proteasomal and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2948455