Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1994-02-28
1998-04-07
Jagannathan, Vasu S.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
514 2, 530303, 530399, C12P 2106, A61K 3830, C07L 1465
Patent
active
057363633
DESCRIPTION:
BRIEF SUMMARY
This invention relates to analogues of human insulin-like growth factor II (IGF-II) and to nucleic acid coding for them.
Human IGF-II belongs to a family of growth factors that includes insulin, relaxin, and insulin-like growth factor I (IGF-I). Members of the family share limited sequence homology but are presumed to exhibit similar structures on the basis of a conserved pattern of disulphide bond formation (Dafgard et al, Journal of Cell Science, 3:53-64 (1984). IGF-I or somatomedin C is a mitogen that mediates the growth-stimulatory effects of growth hormone throughout childhood and adolescence. The role of the related protein IGF-II is more obscure though it has been implicated in regulating brain and muscle development, placental growth and the stimulation of bone and cartilage formation. IGF-II is found at highest levels in bone (1,750 ng/g dry wt.), about a ten fold higher concentration than for IGF-I (190 ng/g dry wt.). Studies involving in situ hybridisation have revealed that both IGF-I and IGF-II mRNA are produced predominantly in cells of mesenchymal origin. This suggests that both IGFs may be involved in paracrine action on multiple cell types throughout development with each IGF having its own spectrum of targets.
The mature form of IGF-II is 67 amino acids in length, its sequence first elucidated by Riner et al, FEBS Letters, 89:293 (1978). The mature molecule is derived from a precursor which includes a 19 amino acid signal peptide and an 89 amino acid C-terminal extension. In addition, a variant form of IGF-II has been described that possesses an extra 3 amino acids in the mature protein. The primary structure of IGF-II is shown in FIG. 1 (SEQ ID NO. 1).
The effects of IGF-II on cells are mediated by at least three different receptors. It has a high affinity for the type I IGF receptor, a membrane bound tyrosine kinase with similar organisation to the insulin receptor. Along with IGF-I, it is likely that the bulk of its effects are mediated by this receptor. IGF-II also binds with high affinity to the type II IGF receptor, a membrane bound protein recently identified as the lysosomal mannose-6-phosphate acceptor (Tong et al., Journal of Biological Chemistry, 263:2585-2588 (1987)). Finally, IGF-II can bind to the insulin receptor, though with lower affinity. It is thought that this last interaction is responsible for the hypoglycaemia caused by certain turnouts that secrete large amounts of IGF-II (Daughaday et al., New England Journal of Medicine, 319:1434-1440 (1988).
A range of pharmacological effects have been demonstrated for IGF-II, both from in vitro and in vivo studies. In vitro, IGF-II stimulates the proliferation of pre-osteoblasts, inhibits the proliferation of mature osteoblasts and stimulates collagen production by mature osteoblasts. In vivo, by osmotic infusion in the rat at 10 .mu.g/day, IGF-II has been found to increase serum/bone alkaline phosphatase levels, increase tibial periosteal bone formation and bone apposition rate, and increase the vertebral forming surface.
The biological effects of both IGF-I and IGF-II are modulated by a number of binding proteins--see Baxter, R. C., Comparative Biochemistry and Physiology, 91B:229-235 (1988). Some of these serve simply as carrier proteins in the serum and amniotic fluid. Others, which are more tissue specific in their distribution, are inhibitory and probably function as autocrine or paracrine regulators of cell growth.
The following patent publications cover various aspects of IGF-II: IGF-II by culturing pituitary cells from a patient with acromegaly. IGF-II and nucleotide sequences of genes encoding them. Various hypotheses for their utility are put forward but nothing concrete by way of clinically useful activity is proposed, at least for IGF-II, other than the treatment of pituitary dwarfism. and prepro-IGF-II, but again gives no clinical utility for the end peptides. no specific clinical utility is disclosed or forecast for IGF-II. healing compositions at a dose which does not produce a systemic insulin-like effect (i.e.
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Bawden Lindsay
Edwards Richard Mark
British Bio-technology Limited
Carlson K. Cochrane
Jagannathan Vasu S.
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