Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2001-04-26
2004-06-29
Kunz, Gary (Department: 1647)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C424S130100, C424S178100
Reexamination Certificate
active
06756480
ABSTRACT:
BACKGROUND OF THE INVENTION
Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) play important physiological roles in calcium homeostasis and in development, respectively. Calcium concentration in the blood is tightly regulated, due to the essential role of calcium in cell metabolism. PTH is an endocrine hormone which is secreted from the parathyroid gland in response to decreased serum calcium levels. PTH acts directly to increase bone resorption and to stimulate renal calcium reabsorption, thus increasing or preserving circulating calcium stores. PTH also indirectly increases calcium absorption in the gut by stimulating the renal hydroxylation of vitamin D.
Both primary and secondary hyperparathyroidism are conditions that are associated with excessive levels of circulating parathyroid hormone. Through the aforementioned pathways, excess PTH levels can cause hypercalcemia and osteopenia. Bone resorption inhibitors such as bisphosphonates and OPG can effectively protect bone and can inhibit the skeleton's contribution to hypercalcemia. However, the calcemic effects of hyperparathyroidism on the kidney and gut are not addressed by currently available therapy.
PTHrP is produced by many cell types, and plays an important role in regulating skeletal development. Postnatally, the roles for PTHrP are less clearly defined. Circulating levels of PTHrP are essentially non-detectable in normal healthy adults. However, many tumors of diverse embryological origins produce and secrete PTHrP in quantities sufficient to cause hypercalcemia. In fact, humoral hypercalcemia of malignancy (HHM) is the most common paraneoplastic syndrome, which accounts for significant patient morbidity and mortality.
Currently, HHM is treated with saline hydration followed by bone resorption inhibitors such as bisphosphonates. This treatment regimen typically takes 3-4 days to achieve significant reductions in serum calcium, and the effects are relatively short-lived (less than one month). For patients with high circulating levels of PTHrP, the effects of current treatment options are even less impressive. Repeated administration of conventional therapies are usually progressively less effective. These limitations to current therapy strongly indicate an unmet medical need for rapid, effective, and long-lasting treatments for HHM.
A major reason for the limited benefits of current HHM therapy is the failure to directly inhibit PTHrP, which is very well established as the principal pathophysiologic factor in HHM. Bone resorption inhibitors such as bisphosphonates only inhibit bone resorption, while PTHrP also has significant calcemic effects on the kidney and the gut. Total neutralization of PTHrP would be the ideal adjuvant therapeutic approach to treatment of HHM.
Both PTH and PTHrP interact with PTH-1 receptor, which accounts for most of their known effects. Mannstadt et al. (1999),
Am. T. Physiol.
277. 5Pt 2. F665-75 (1999). Only PTH interacts with the newly discovered PTH-2 receptor. Id. PTHrP can be changed to a PTH-2 receptor agonist, however, by changing two residues to the residues at those positions in PTH. Gardella et al. (1996),
J. Biol. Chem.
271 (33): 19888-93.
An N-terminal fragment of PTH has been used as a therapeutic agent. Intermittently administered native PTH-(1-84) exhibits osteogenic properties, and it has been recognized for decades that these properties can be fully realized with the C-terminally truncated fragment PTH-(1-34). Both peptides bind and activate the PTH-1 receptor with similar affinities, causing the activation of adenylate cyclase (AC) as well as phospholipase C (PLC). AC activation through PTH-1 receptor generates cAMP, while PLC activation through PTH-1 receptor generates PKC and intracellular calcium transients. PTH-(1-34) can maximally activate both the AC and the PLC pathways. It has been demonstrated that the anabolic effects of PTH-(1-34) require short intermittent (daily) exposures Dobnig (1998),
Endocrinol.
138: 4607-12. In human trials on postmenopausal women, daily subcutaneous injection of low doses of PTH(1-34) were shown to result in impressive bone formation in the spine and femoral neck with significant reduction in incidence of vertebral fractures. These clinical data reveal PTH as one of the most efficacious agents tested for osteoporosis.
Truncated PTH fragments have diminished AC/cAMP activation and similarly diminished anabolic activity. Rixon et al. (1994),
J. Bone Min. Res.
9: 1179-89; Hilliker et al. (1996), Bone 19: 469-477; Lane et al. (1996),
J. Bone Min. Res.
11: 614-25. Such truncated PTH fragments have this diminished activity (Rixon et al. (1994); Hilliker et al. (1996); Lane et al. (1996)) even if they maintain full agonism towards PKC. Rixon et al., (1994). These observations have led to the proposal that the AC/cAMP pathway is critical for the bone anabolic properties of PTH, while the PLC/PKC pathway is dispensable in this regard. Rixon et al, (1994); Whitfield et al. (1996),
Calcified Tissue International
53: 81-7.
An opposing, but not mutually exclusive, theory suggests that PLC activation (in addition to AC) might also be an important property of anabolic PTH fragments. Takasu (1998),
Endocrinol.
139: 4293-9. The apparent absence of PLC activation by some anabolic C-terminally truncated PTH peptides may be an artifact of insensitive assay methods combined with lower receptor binding. Takasu (1998). Progressive truncations from the C-terminus of PTH-(1-34) result in stepwise reductions in binding affinity for the PTH1R Takasu (1998). PKC activation through PTH-1 receptor appears to be acutely sensitive to binding affinity and to receptor density (Guo et al. (1995),
Endocrinol
136: 3884-91), whereas cAMP activation is far less sensitive to these variables. As such, hPTH-(1-31) has a slightly reduced (1-6 fold) affinity for PTH-1 receptor compared to hPTH-(1-34), while hPTH-(1-30) has a significantly reduced (10-100 fold) affinity Takasu (1998). Perhaps due to this decreased PTH-1 receptor affinity, PTH-(1-30) is a weak and incomplete agonist for PLC activation via the rat PTH-1 receptor.
Compared to PTH-(1-34), PTH-(1-31) has similar or slightly reduced anabolic potential (Rixon et al. (1994); Whitfield et al. (1996),
Calcified Tissue International
53: 81-7; Whitfield et al. (1996),
Calcified Tissue International
65:143-7), binding affinity for PTH1R, and cAMP induction (Takasu (1998)). PTH-(1-31) also has slightly reduced PLC activation. Takasu (1998). In healthy humans, infusion of PTH-(1-31) and PTH-(1-34) had similar stimulatory effects on plasma and urinary CAMP concentration, but unlike PTH-(1-34), PTH-(1-31) failed to elevate serum calcium, plasma 1,25(OH)2D3, or urinary N-TX levels. Fraher et al. (1999),
J. Clin. Endocrin. Met.
84: 2739-43. These data suggest that PTH-(1-31) has diminished capacity to induce bone resorption and to stimulation vitamin D synthesis, which is a favorable profile for bone anabolic agents.
PTH-(1-30) was initially shown to lack anabolic properties Whitfield et al. (1996),
Calcified Tissue International
53: 81-7. More recently, however, it has been demonstrated that PTH-(1-30) is anabolic when administered at very high doses (400-2,000 &mgr;g/kg, vs. 80 &mgr;g/kg for PTH-(1-34)). The lower potency of PTH-(1-30) could be predicted by its lower binding affinity for PTH-1 receptor, its diminished CAMP activation, and/or to its greatly diminished PKC activation. Takasu (1998). It remains to be determined whether PTH-(1-30) has a similar or even more desirable reduction in apparent bone resorption activity.
PTH-(1-28) is the smallest reported fragment to fully activate CAMP. Neugebauer et al. (1995),
Biochem.
34: 8835-42. However, hPTH-(1-28) was initially reported to have no osteogenic effects in OVX rats. Miller et al. (1997),
J. Bone Min. Res.
12: S320 (Abstract). Recently, a very high dose of PTH-(1-28) (1,000 &mgr;g/kg/day) was shown to be anabolic in OVX rats, whereas 200 &mgr;g/kg/day was ineffective. Whitfield et al. (2000),
J. Bone Min. Res.
15
Kostenuik Paul
Lacey David Lee
Liu Chuan-Fa
Amgen Inc.
Kunz Gary
Nichols Christopher James
Watt Stuart L.
Winter Robert B.
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