Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-09-03
2003-06-24
Brumback, Brenda (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S011400, C514S012200, C530S307000, C530S317000, C530S324000
Reexamination Certificate
active
06583114
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to methods of bone healing and fracture repair.
2. Background Information
Approximately 8-10 million bone fractures are reported annually in the United States with more than 1 million of these requiring hospitalization. The estimated annual costs of treating these fractures exceeds 20 billion dollars. While this is already significant, these numbers are expected to increase due to the aging of the general population. Even though several therapies are indicated for preventing the bone loss associated with aging, there are fewer therapies indicated for treatment once a fracture has occurred. Most of these require local administration which is undesirable due to the complexity of delivery and poor patient compliance. Therefore, it would be desirable to have additional methods of facilitating bone healing and fracture repair.
It has recently been reported that intermittent treatment with parathyroid hormone (PTH) improves fracture healing in ovariectomized rats, indicating that PTH treatment may be potentially useful in treating postmenopausal osteoporotic fractures. “Effect of Recombinant Human (1-84) Parathyroid Hormone on Fracture Healing in Ovariectomized Rats,” H. W. Kim et al.;
Transactions of the
43
rd Annual Meeting of the Orthopaedic Research Society
, Vol. 22, Section 1, Abstract 181-31, Feb. 9-13, 1997, and “Intermittent Treatment of PTH Improves Fracture Healing in OVX Rat,” H. W. Kim et al.;
Journal of Bone and Mineral Research
, Vol. 11, Supplement 1, page S152, Abstract P248 (August 1996). Other investigators have reported that implantation of a gene activated matrix expressing bone morphogenetic protein-4 and/or a fragment of PTH (amino acids 1-34) into the segmented defect rat fracture model causes formation of new bone which bridges the gap more rapidly than an untreated control. “Stimulation of New Bone Formation by Direct Transfer of Osteogenic Plasmid Genes,” Jianming Fang et al.;
Proc. Natl. Acad. Sci
. (
USA
), Vol. 93:5753-5758 (June 1996). Various PTH analogs have also been reported to be useful for treatment of osteoporosis (U.S. Pat. Nos. 5,556,940 and 5,559,792). Other methods of fracture healing include the use of is human platelet factor 4 (U.S. Pat. No. 5,622,935), benzothiophenes (U.S. Pat. No. 5,502,074) and 24,25(OH)
2
vitamin D
3
(U.S. Pat. No. 5,069,905).
PTH related peptide (PTHrP), previously known as the factor responsible for humoral hypercalcemia of malignancy, is a peptide of 138-174 amino acids (depending on alternative splicing) which binds to the PTH/PTHrP receptor. The N-terminal 34 amino acid sequence of PTHrP is of limited sequence homology to that of PTH, but in certain cases shows similar activity to PTH. However, PTHrP is generally less potent and less bone anabolic than PTH and has not been associated with fracture healing. The sequence of hPTHrP (1-34) is as follows:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile
1 5 10 15
Gln Asp Leu Arg Arg Arg Phe Phe Leu His His Leu Ile Ala Glu
20 25 30
Ile His Thr Ala (SEQ ID NO:1).
Several truncated homologs and analogs of PTHrP have been reported. Analogs in which amino acid residues 22-31 of PTHrP(1-34) are replaced by an amphipathic &agr;-helix (U.S. Pat. No. 5,589,452 and WO 97/07815) and related derivatives have been described as useful for treating osteoporosis. “RS-66271, A C-terminally Substituted Analog of Human Parathyroid Hormone-Related Protein (1-34) Increases Trabecular and Cortical Bone in Ovariectomized, Osteopenic Rats,” B. H. Vickery et al.
J. Bone
&
Mineral Research,
11(12):1943-1951 (1996) and “Modulation of Osteogenic Cell Ultrastructure by RS-23581, an Analog of Human Parathyroid Hormone (PTH)-Related Peptide-(1-34) and Bovine PTH-(1-34),” D. Leaffer et al.
Endocrinology,
136(8):3624-3631 (1995). Monocyclic and bicyclic analogs of PTHrP (1-34) and PTHrP(7-34) were shown to bind strongly to the PTH receptor and stimulate (or antagonise) PTH-stimulated adenyl cyclase activity in osteoblast-like cells. “Mono- and Bicyclic Analogs of Parathyroid Hormone-Related Protein. 1. Synthesis and Biological Studies,” Michael Chorev et al.
Biochemistry,
36:3293-3299 (1997), and “Cyclic analogs of PTH and PTHrP,” WO 96/40193.
SUMMARY OF THE INVENTION
In one aspect, this invention provides methods of bone healing and fracture repair comprising administering to a patient in need thereof an effective amount of a polypeptide analog of parathyroid hormone related peptide (PTHrP) and salts thereof, wherein amino acid residues 22-31 form an amphipathic &agr;-helix composed of hydrophilic amino acids (Haa) and lipophilic amino acids (Laa) ordered in the sequence:
Haa(Laa Laa Haa Laa)
2
Laa
When illustrative embodiments of this amphipathic helix are inserted into the PTHrP sequence, particularly into N-terminal truncates of human PTHrP (residues 1-32 through 1-38), the resulting polypeptides are effective in bone healing and fracture repair. Systemic administration is a preferred mode of delivery.
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Bilezikian, John P. et al, Eds., “Part I Basic Principles,” Principles of Bone Biology, 412-413.
Hock, JM. et al., “Comparison of the Anabolic Effects of Synthetic Parathyroid Hormone-Related Protein (PTHrP) 1-34 and PTH 1-34 on bone in Rats,” Endocrinology, vol. 125, 2022-2207, (1989).
Lanske, B. et al., “The Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mediates Actions of Both Ligands in Murine Bone,” Endocrinology, vol. 139., No. 12, 5194-5204 (1998).
Pilbeam, C.C. et al., “Comparison of the Effects of Various Lengths of Synthetic Human Parathyroid Hormone-Related Peptide (hPTHrP) of Malignancy on Bone Resoprtion and Formation in Organ Culture,” Bone, vol. 14, 717-720 (1993).
Mierke, et al., “Conformational Studies of Mono-and Bicyclic Parathyroid Hormone-Related Protein-Derived Agonists,”Biochemistry, (1997) pp 10372-10383, vol. 36.
Bisello, et al.,Biochemistry, vol. 36, 1997, pp 3293-3299, “Mono-and Bicyclic Analogs of Parathyroid Hormone-Related Protein. 1. Synthesis and Biological Studies”.
Fang, et al.,Proc. Natl. Acad. Sci.(U.S.A.), vol. 93, Jun. 1996, pp 5753-5758, “Stimulation of new bone formation by direct transfer of osteogenic plasmid genes”.
Chorev, et al.,Biochemistry, vol. 30, 1991, pp 5968-5974, “Cyclic Parathyroid Hormone Related Protein Antagonists: Lysine 13 to Aspartic Acid 17 [i+4)] Side Chain Lactamization”.
Kim, et al., 43rd Annual Meeting,Orthopaedic Research Soc., Feb. 9-13, 1997, San Francisco, California, vol. 22, Section 1, “Effect of Recombinant Human (1-84) Parathyroid Hormone on Fracture Healing in Ovariectomized Rats”.
Kim, et al.,Journal of Bone and Mineral Research, vol. 11:Supplement 1, Aug
Brumback Brenda
Gupta Anish
Peries Rohan
Roche Palo Alto LLC
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