Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Hormones – e.g. – prolactin – thymosin – growth factors – etc.
Patent
1990-02-12
1999-01-12
Walsh, Stephen
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Hormones, e.g., prolactin, thymosin, growth factors, etc.
530350, C07K 1450
Patent
active
058592083
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The invention relates to recombinant production of growth factors important for constructing vascular systems in healing tissues and inhibiting abnormal persistent angiogenesis. In particular, analogs of genes encoding human basic and acidic fibroblast growth factors (FGF) are cloned and expressed.
BACKGROUND ART
The process of healing when tissue is subjected to trauma, such as wounding or burns, is an extremely complex one, but it is known to be mediated by a number of protein factors. These factors are essential to the growth and differentiation of the cells which serve to replace the tissue destroyed. A number of candidate factors have been identified on the basis of the ability of extracts from various tissues, such as brain, pituitary, and hypothalamus, to stimulate the mitosis of cultured cells. Numerous shorthand names have been applied to the active factors in these extracts, including platelet-derived growth factor (PDGF), macrophage-derived growth factor (MDGF), epidermal growth factor (EGF), tumor angiogenesis factor (TAF), endothelial cell growth factor (ECGF), fibroblast growth factor (FGF), hypothalamus-derived growth factor (HDGF), retina-derived growth factor (RDGF), and heparin-binding growth factor (HGF). (See, for example, Hunt, T. K., J Trauma (1984) 24:S39-S49; Lobb, R. R., et al,Biochemistry (1984) 23:6295-6299).
Folkman, J., et al, Science (1983) 221:719-725, reported that one of the processes involved in wound healing, the formation of blood vessels, is profoundly affected in tumors by heparin. From this and other studies, it is clear that heparin specifically binds to protein(s) associated with a number of these growth factor activities, and therefore heparin has been used as a purification tool. It has been shown that the affinity of some growth factors for heparin is independent of overall ionic charge, since both positively and negatively charged factors are bound (Maciag, T., et al,Science (1984) 225:932-935; Shing, Y., et al, Science (1984) 223:1296-1299; Klagsbrun, M., et al, Proc Natl Acad Sci (USA) (1985) 82:805-809). The capacity to bind or not to bind to heparin is one measure of differentiation between the activities in the various extracts. For example, EGF and PDGF do not bind strongly to heparin; in fact, EGF does not bind to heparin at all. The other factors above do show strong heparin binding. However, it is believed that acidic brain FGF, ECGF, RDGF, and HGF-alpha are in fact the same factor. Similarly, it is also believed that pituitary FGF, cationic brain FGF, TAF, and HGF- are the same protein. (Lobb, R. R., et al (supra)). A summary and comparison of thirteen endothelial growth factors which have been purified using heparin affinity is found in Lobb, R., et al, J Biol Chem (1986) 261:1924-1928.
Using heparin affinity chromatography, basic fibroblast growth factors exhibiting a potent mitogenic activity for capillary endothelium have been isolated from rat chondrosarcoma (Shing, Y., et al, supra) and from bovine cartilage (Sullivan, R., et al, J Biol Chem (1985) 260:2399-2403). Thomas, K. A, et al, Proc Natl Acad Sci (USA) (1984) 81:357-361, U.S. Pat. No. 4,444,760, purified two heterogeneous forms of an acidic bovine brain fibroblast growth factor having molecular weights of 16,600 and 16,800 daltons. Gospodarowicz and collaborators have shown the presence in both bovine brains and pituitaries of basic fibroblast growth factor activities and purified these proteins using heparin-affinity chromatography in combination with other purification techniques (Bohlen, P., et al, Proc Natl Acad Sci (USA) (1984) 81:5364-5368; Gospodarowicz, D., et al (ibid) 6963-6967). These factors also have molecular weights of approximately 16 kd, as does a similar factor isolated from human placenta (Gospodarowicz, D., et al, Biochem Biophys Res Comm (1985) 128:554-562).
The complete sequence for basic FGF derived from bovine pituitary has been determined (Esch, F., et al, Proc Natl Acad Sci (USA) (1985) 82:6507-6511). Homogeneous preparations were obtained and
REFERENCES:
patent: 4959314 (1990-09-01), Mark et al.
Abraham et al., "Human basic fibroblast growth factor: nucleotide sequence and genomic organization" EMBO J. (1986) 5:2523-2528.
Fiddes et al., "Isolation and characterization of clones encoding basic and acidic fibroblast growth factors" J. Biol. Chem. (1986) 0:149 (No. 10, Part C, abstract No. L146).
Seno et al. Biochem Biophs Res Comm 151:701-708 (1988).
Baird et al. Rec Prog Horn Res 42:143-705 (1986).
Abraham Judith A.
Fiddes John C.
Protter Andrew A.
Lehnhardt Susan K.
Walsh Stephen
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