Insulin-like growth factor binding protein (IGFBF-5)

Details Insulin-like growth factor binding protein (IGFBF-5) Insulin-like growth factor binding protein (IGFBF-5)

1994-11-28

2002-12-31

Carlson, Karen Cochrane (Department: 1653)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

C435S320100, C435S252300, C435S325000, C536S023100, C530S350000, C530S303000, C530S387100, C530S388100, C514S002600, C514S003100

Reexamination Certificate

active

06500635

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Disclosure
The present invention relates generally to production of polypeptides from recombinant DNA molecules encoding such polypeptides. More specifically, this invention relates to a new insulin-like growth factor binding protein (designated herein as IGFBP-5), recombinant DNA molecules encoding this polypeptide, and methods for producing IGFBP-5 from recombinant host cells.
2. Description of the Related Art
Insulin-like growth factors (IGFS) are low molecular weight polypeptide hormones with structural homology to proinsulin. Two different IGFs are known, namely IGF-I and IGF-II, which are mitogenic in vitro for a wide variety of cells in tissue culture. Both IGFs stimulate in vitro the growth of various tissues and in particular they induce collagen synthesis. IGF-I mediates the growth promoting effect of growth hormone in chondrogenesis and bone formation and is therefore essential for normal growth of an individual. This is demonstrated by the fact that pygmies and toy poodles are deficient in IGF-I but have normal growth hormone level in their serum. IGF-II is believed to play a key role in fetal development and nerve growth.
In addition to their primary effect on skeletal tissue IGFs also exhibit growth-stimulating functions on other tissues. Wound fibroblasts are known to produce IGFs which are effective in stimulating fibroblasts to grow and synthesize collagen, a structural protein normally required for wound healing. Vascularization of the wound tissue is also induced. Further, it has also been found that IGFs have an erythropoietin-like activity in that they induce hematopoiesis.
Recent studies have also demonstrated that IGFs produced by certain cancer cells, e.g. breast and kidney cancer cells, auto-stimulate the proliferation of cancer cells and the vascular and fibrous tissues required to support the growth of cancer tissues.
In addition to this, both IGFs show a spectrum of metabolic activities similar to those of insulin, in that they stimulate, in particular, the transport and metabolism of glucose. The biological effects of IGFs and insulin are mediated through their binding to specific receptors. In particular, both IGFs have the ability to bind to the insulin receptor with approximately 100-fold lower affinity than does insulin.
Both IGFs have a concentration in blood approximately a hundred-fold higher than that of insulin. Hypoglycemia is prevented by a regulatory mechanism which involves carrier proteins present in blood and able to form complexes with IGFs. Thus, IGFs circulate in the blood in the form of a complex which has no insulin-like activity.
Through their association with carrier proteins (hereinafter referred to as IGF binding proteins or ICFBPs), binding of IGFs to cell surface receptors is inhibited. It has also been demonstrated that another function of the IGF binding proteins is to increase the short half-life of IGFs, which are subjected to rapid proteolytic degradation when present in the free form in blood.
In accordance with the foregoing, IGFs may be useful in vitro to stimulate a) the growth of animals and humans with growth hormone deficiency, b) tissue regeneration, such as erythropoiesis and chondrogenesis, c) wound healing and d) the functions of various organs e.g. liver or kidney. As a result of their chondrogenesis stimulating activity, IGFs are of particularly suitable use for bone formation, e.g. in the treatment of osteoporosis.
IGFs for use in the above-referred treatments are advantageously administered to a subject in association with at least one IGF binding protein. Through their association with carrier proteins (hereinafter referred to as IGF binding proteins or IGFBPs), binding of IGFs to cell surface receptors is inhibited. It has also been demonstrated that another function of the IGF binding proteins is to increase the short half-life of IGFs, which are subjected to rapid proteolytic degradation when present in the free form in blood.
Administration of the combination of IGF and an IGF binding protein, rather than IGF alone, has beneficial effects including the prevention of hypoglycemia and possible mitogenic effects at injection sites and the prolongation of IGF half-life. Furthermore, it has been found that binding proteins are also useful for potentiating the erythropoietin like-effect of IGF-I. The binding proteins may also be useful for targeting IGFs to specific tissues.
When administered alone, i.e., without any IGF, the binding proteins may also be therapeutically useful for blocking the adverse effects of IGFs, such as those which occur when IGFs are produced in excess, e.g. free IGFs secreted by certain cancer cells e.g. hormone-producing cancer cells such as breast or kidney cancer cells. IGF binding protein therapy may also prevent blindness as a secondary effect of diabetic proliferation retinopathy. Indeed it has been shown that IGFs may be one of the factors stimulating endothelial and fibroblast proliferation in diabetic retinopathy.
Another therapeutic use of IGFBPs is the control of excessive growth in IGF binding protein-deficient subjects, since it is very likely that high IGF levels combined with abnormally low levels of binding protein are responsible for excessive growth.
Known forms of IGFBPs include IGFBP-1, having a molecular weight of approximately 30-40 kd in humans. See, e.g., Povoa, G. et al., Eur. J. Biochem (1984) 144:199-204, relates to IGFBP-1, isolated and purified from amniotic fluid; Koistinen, R. et al., Endocrinology (1986) 118:1375-378, relates to IGFBP-1 isolated and purified from: human placenta; Powell, D. R. et al., J. Chromatogr. (1987) 420:163-170, relates to a 30-40 kd IGFBP-1 isolated and purified from conditioned medium of hepatoma G2 (Hep-G2) cells; Lee, Y. L. et al., Mol. Endocrinol. (1988) 2:404-411, relates to an amino acid sequence of IGFBP-1 isolated from Hep-G2 cells; Brinkman, A. et al., The EMBO Journal (1988) 7: 2417-2423, relates to an IGFBP-1 placental cDNA library; Brewer, M. T. et al., Bioch. Biophys. Res. Com. (1988) 152:1289-1297, pertains to nucleotide and amino acid sequences for IGFBP-1 cloned from a human uterine decidua library; WO89/09792, published Oct. 19, 1990, Clemmons, D. R., et al., pertains to cDNA sequences and cloning vectors for IGFBP-1 and IGFBP-2; WO89/08667, published Sept. 21, 1989, Drop, L. S., et al., relates to an amino acid sequence of insulin-like-growth factor binding protein 1 (IGFBP-1); WO89/09268, published Oct. 5, 1989, Baxter, R. C., relates to a cDNA sequence of IGFBP-1 and methods of expression for IGFBP-1.
IGFBP-2 has a molecular weight of approximately 33-36 kd. See, e.g., Binkert, C. et al., The EMBO Journal (1989) 8:2497-2502, relates to a nucleotide and deduced amino acid sequence for IGFBP-2.
IGFBP-3 has a molecular weight of 150 kd. See, e.g., Baxter, R. C. et al., Bioch. Biopys. Res. Com. (1986) 139:1256-1261, pertains to a 53 kd subunit of IGFBP-3 that was purified from human serum; Wood, W. I. et al., Mol. Endocrinol. (1988) 2:1176-1185, relates to a full length amino acid sequence for IGFBP-3 and cellular expression of the cloned IGFBP-3 cDNA in mammalian tissue culture cells; WO90/00569, published Jan. 25, 1990, Baxter, R. C., relates to isolating from human plasma an acid-labile subunit (ALS) of (IGFBP) complex and, the particular amino acid sequence for ALS pertains to a subunit of IGFBP-3.
For nonhuman forms, see, e.g., Mottola, C. et al., Journ. of Biol. Chem. (1986) 261: 11180-11188, relates to a non-human form of IGFBP that was isolated in conditioned medium from rat liver BRL-3A cells and has a molecular weight of approximately 33-36 kd; Lyons, R. M. et al., Mol. Cell. Endocrinol. (1986) 45: 263-270, relates to a 34 kd cloned BRL-3A rat liver cell protein designated MCP; EPO Publ. No. 369 943, published May 23 1990, Binkert, C., et al., relates to a cDNA sequence of the rat BRL-3A binding protein and uses this sequence to screen three human cDNA libraries.
Mohan, S. et al., Proc. Natl. Acad. Scii. (1989) 86:8338-8342, relates to an N-terminal amin

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