Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
2000-08-24
2002-11-19
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S085100, C424S184100, C424S192100, C424S178100, C514S002600, C514S008100, C514S012200, C514S885000, C530S350000, C530S351000
Reexamination Certificate
active
06482411
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of cell biology and bone metabolism. More particularly, it concerns the use of compositions containing one or more CD40 agonists, such as CD40 ligands and/or agonistic anti-CD40 antibodies, to reduce or prevent cell death or apoptosis, in bone cells, such as osteocytes and osteoblasts. Methods of treating or preventing bone loss, including osteoporosis, and methods of reducing or eliminating the bone loss associated with steroid administration are also included. Further provided are a variety of therapeutic kits and cocktails.
2. Description of Related Art
In the body, bone is remodeled continuously through the process of resorption by osteoclasts, followed by bone formation by osteoblasts. Normally, the activity of these two types of cells is balanced through the action of hormones and other signaling mechanisms. During the resorption phase, sites for remodeling are targeted by osteoclasts that form pits in bone, releasing organic matrix and minerals into the circulation. Resorption at a single site can last as long as about three weeks. As resorption progresses, osteoblasts begin filling in the resorbed region with new mineralized bone.
Peak bone mass is reached at about age 30. After pe tne mass is reached, there is a gradual age-related loss of bone mass in both males and females due to a slight imbalance in resorption and formation. However, as estrogen production declines in women around the time of menopause, bone resorption increases dramatically, which can lead to rapid bone loss. Premenopausal women have been shown to turnover bone at a rate of about one-third to one-half gram of bone per day, while the turnover is double to triple that in early postmenopausal women. Although bone loss can be especially elevated in the five to seven years immediately following menopause, this process continues throughout life. The rate of bone loss can vary dramatically from woman to woman.
Several studies have documented this dramatic increase in bone turnover levels at menopause (Ebeling et al., 1996; Garnero et al., 1996; Prestwood et al., 1994). The results showed that the increase in both the mean and the range of bone resorption values stayed high for more than 20 years beyond menopause, a pattern consistent with bone mass changes over a woman's lifetime. These studies demonstrated an inverse correlation between bone turnover and bone mass, with high turnover associated with low bone mass.
Postmenopausal bone loss may be due to increased production of cytokines such as TNF&agr; and interleukin 1 and/or increased osteocyte apoptosis. Estrogen has been shown to be a viability factor for osteocytes in both humans and rats (Tomkinson et al., 1997, 1998). Human bone removed from female patients being treated with gonadotropin releasing hormone showed a higher increase in the proportion of dead osteocytes compared to controls. The same was shown to be true for ovariectamized rates compared to controls (Rickard et al., 1992). Estrogen has been reported to modulate TNF&agr; production by human osteoblast and peripheral monocytes from women who have undergone ovariectomy and produce increased levels of TNF&agr; (Pacifici et al., 1991). Delivering both IL-1 receptor antagonist and the soluble TNF receptor completely blocked bone loss due to ovariectomy in mice (Kimble et al., 1995). Therefore, a lack of estrogen can lead to increased production of cytokines responsible for bone loss (Lorenzo, 1996).
In addition to bone loss due to aging and estrogen deficiency, patients of all ages, both sexes, and all races are susceptible to steroid-induced bone loss. Administration of glucocorticoids and steroids is the third most common cause of osteoporosis. Steroid-induced bone loss usually affects the cortical and cancellous bone of the axial skeleton. Between 30% and 50% of individuals taking steroids for more than 6 months will develop osteoporosis. The rate of bone loss is very rapid in the initial year of therapy, with as much as 20% of the bone lost in the first year. Doses exceeding 7.5 mg/day of prednisone can cause significant loss of trabecular bone in most people.
Studies in mice administered glucocorticoids suggests that steroid-induced bone loss is due to decreased bone formation which results from higher numbers of apoptotic/dead osteoclasts and osteoblasts. Lesser numbers of these cells could account for changes seen with glucocorticoid-induced bone disease. A decrease in osteoblast and osteocyte cell number due to death/apoptosis has also been demonstrated in patients who have glucocorticoid-induced osteoporosis (Weinstein et al., 1998).
Despite the current understanding and the considerable amount of research in this area, bone loss and osteoporosis remain significant medical and economic problems. Therefore, methods of reducing or preventing bone loss, for example by reducing or preventing apoptosis of osteocytes and osteoblasts, would represent a significant advance in the art.
SUMMARY OF THE INVENTION
The present invention overcomes one or more of these and other shortcomings in the art by providing a range of new treatments by which to reduce bone cell death and bone loss. The invention is broadly based upon the surprising finding that CD40 is expressed on bone cells and that CD40 agonists dramatically reduce bone cell death. The invention thus provides methods, compositions and uses of one or more CD40 agonists, such as CD40 ligands and/or agonistic anti-CD40 antibodies, to reduce or prevent bone cell death or apoptosis, thereby providing new treatments for bone loss associated with a variety of diseases and clinical conditions.
The invention therefore provides methods, compositions and uses in reducing or preventing bone cell death and/or apoptosis, comprising contacting a bone cell, a population of bone cells or a cell population comprising bone cells, with a biologically effective amount of at least a first composition comprising at least a first CD40 agonist, such as a CD40 ligand and/or agonistic anti-CD40 antibody.
The bone cells to be treated by the invention include, but are not limited to, osteoblasts and osteocytes. The CD40 ligands and/or agonists may induce the apoptosis of osteoclasts, inhibit the apoptosis of osteoclasts, or exert no detectable effects on osteoclasts, so long as the overall effect of the CD40 ligand and/or agonist inhibits the apoptosis of osteocytes and/or osteoblasts to a greater extent than osteoclasts, or otherwise produces a net beneficial effect on bone mass, bone density, bone cell number or other parameter indicative of health bone tissue.
All CD40 agonists are suitable for use in the invention, so long as they bind to and activate one or more CD40 receptors on a bone cell. A CD40 agonist that “binds to and activates” a CD40 receptor a bone cell is a biological or chemical component or agent that stimulates cell signaling via CD40 in such cells. “Cell signaling” via a CD40 receptor is indicated by the capacity to “transduce” a signal, i.e., transmit a biological effect, to the intracellular environment by binding of an agent to an extracellular portion of the receptor. Most preferably, CD40 agonists bind to and activate a CD40 receptor on a bone cell, thereby creating a cell signal that reduces cell death and/or apoptosis in the cell.
Agents that “stimulate” cell signaling via CD40 receptors may do so directly or indirectly. Although agents that act directly are generally preferred, agents that indirectly stimulate or activate CD40 receptors may be used, including accessory signaling molecules, co-stimulators and the like, and agents that remove, inactivate or downregulate inhibitors of the CD40 signaling process. Included within this group of CD40 agonists are agents that stimulate or “upregulate” the expression of the CD40 receptor on bone cells. Such components will therefore increase the amount of the receptor expressed at the cell surface and available for binding to the natural biological ligand counterpart or exogenousl
Ahuja Seema A.
Bonewald Lynda F.
Board of Regents , The University of Texas System
Gambel Phillip
Williams, Morgan and Amerson
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