Drug – bio-affecting and body treating compositions – Lymphokine
Patent
1996-11-27
2000-07-11
Kemmerer, Elizabeth
Drug, bio-affecting and body treating compositions
Lymphokine
514 2, A61K 3818
Patent
active
06086866&
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND
Human platelet-derived growth factor ("PDGF") is believed to be the major mitogenic growth factor in serum for connective tissue cells. The mitogenic activity of PDGF has been documented in numerous studies, wherein PDGF has been shown to positively affect mitogenesis in arterial smooth muscle cells, fibroblast cells lines, and glial cells. Deuel et al., J. Biol. Chem., 256(17), 8896-8899 (1981). See also, e.g., Heldin et al., J. Cell Physiol., 105, 235 (1980) (brain glial cells); Raines and Ross, J. Biol. Chem., 257, 5154 (1982) (monkey arterial smooth muscle cells). PDGF is also believed to be a chemoattractant for fibroblasts, smooth muscle cells, monocytes, and granulocytes. Because of its apparent abilities to both induce mitogenesis at the site of connective tissue wounds, and to attract fibroblasts to the site of such wounds, PDGF is thought to have particular potential for therapeutic use in the repair of injured, or traumatized, connective tissues.
Other members of the PDGF family include vascular endothelial cell growth factor ("VEGF", sometimes also referred to as "vascular permeability factor, or "VPF") and placental growth factor ("PLGF"). Tischer et al., Biochem. Biophys. Res. Comm., 165(3), 1198-1206 (1989) and Maglione et al., Proc. Natl. Acad. Sci. USA, 88, 9267-9271 (1991), respectively. Both VEGF and PLGF form disulfide bonded dimers from the eight highly conserved cysteine residues that appear in the PDGF homologous region of each monomeric unit of these PDGF family members. Tischer et al. and Maglione et al., ibid. The receptors for VEGF and PLGF are also in the same receptor subfamily as the PDGF receptors. Consequently, these "newer" members of the PDGF family are thought to be potentially useful as therapeutic products in wound repair, although they have not been studied as extensively as PDGF.
Naturally occurring PDGF is a disulfide-bonded dimer having two polypeptide chains, namely the "A" and "B" chains, with the A chain being approximately 60% homologous to the B chain. Naturally occurring PDGF is found in three dimeric forms, namely PDGF-AB heterodimer, PDGF-BB homodimer, or PDGF-AA homodimer. Hannink et al., Mol. Cell. Biol., 6, 1304-1314 (1986). Although PDGF-AB has been identified as the predominate naturally occurring form, it is the PDGF-BB homodimer that has been most widely used in wound healing studies. Each monomeric subunit of the biologically active dimer, irrespective of whether it is an A chain monomer or a B chain monomer, contains eight cysteine residues. Some of these cysteine residues form interchain disulfide bonds which hold the dimer together.
The PDGF-B found in human platelets has been identified as a 109 amino acid cleavage product (PDGF-B.sub.109) of a 241 amino acid precursor polypeptide Johnsson et al., EMBO Journal, 3(5), 921-928 (1984). This 109 amino acid homologous sequence coincides with the 109 amino acid cleavage product of the c-sis encoded PDGF-B precursor protein and is believed by many to be the mature form of PDGF in humans. Homology with the c-sis encoded precursor protein begins at amino acid 82 of the 241 amino acid precursor protein and continues for 109 amino acids. Another form of PDGF-B (PDGF-B.sub.119), corresponding to the first 119 amino acids of the c-sis encoded PDGF-B precursor protein, has also been identified as a major cleavage product of the c-sis encoded precursor protein when the entire c-sis gene is encoded into a transfected mammalian host. U.S Pat. No. 5,149,792.
The application of PDGF to dermal wounds, including incisional wounds and dermal ulcers, in human and/or animals has been shown to accelerate the rate at which these types of wounds heal. Pierce et al, 167, J. Exp. Med., 974-987 (1988) (incisional wounds in rats); Robson et al., The Lancet, 339, 23-25 (1992) (human dermal ulcers). PDGF has is believed to function in the acceleration of wound healing by stimulating the deposition of a provisional matrix in the wound bed. Pierce et al., Am. J. Pathology, 140(6), 1375-1388 (1992). PDGF is also believe
REFERENCES:
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