Growth hormone potentiating molecules

Details Growth hormone potentiating molecules Growth hormone potentiating molecules

1995-04-25

1998-12-01

Achutamurthy, Ponnathapura

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Conjugate or complex

4241931, 4241851, 4241841, 530329, 530311, 530317, A61K 3900, C07K 1461, C07K 707

Patent

active

058434534

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to biologically active molecules, particularly peptides. More particularly, the invention relates to peptide fragments of growth hormone (including bovine growth hormone (bGH), porcine growth hormone (pGH), chicken growth hormone (cGH), ovine growth hormone (oGH) and their mutant derivatives), which are rendered antigenic and which can enhance or promote growth hormone activity. Human growth hormone (hGH), rat growth hormone (rGH), mouse growth hormone (mGH), horse growth hormone (eGH) and salmon growth hormone (sGH) are other growth hormones of interest.
Polypeptide hormones are important for both medical and veterinary application. One such hormone, growth hormone, is found in vertebrates and is important for promoting somatic growth. Growth hormones from different species share both structural and functional characteristics. Growth hormones consist of amino acid sequences generally of about 191 residues in length. It is known that growth hormone can stimulate somatic growth, promote wool growth in sheep, affect body composition, improve food efficiency and promote lactation in appropriate species. Different aspects of the structural and functional characteristics of growth hormones have been described (Nicoll et al, Endocrine Rev. 7(2) 169-203 (1986); Isaksson et al, Ann. Rev. Physiol. 47 483-499 (1985); Wallis, "Chemistry and Biochemistry of Amino Acids, Peptides and Proteins" (Ed. B. Weinstein), Vol. 5, pp 213-320 (Dekker, New York (1978)).
Antibodies to hormones have been shown to be capable of (i) enhancing hormone activity, (ii) have no effect on hormone activity or (iii) inhibit hormone activity (Thompson, Proc. Soc. Expl. Biol. NY 35 640-644 (1937); Rolands, J. Endocrinol. 1 177-183 (1939); Goodfriend et al, J. Clin. Endocrinol. Metab. 30 565-572 (1970); Schechter et al, Proc. Natl. Acad. Sci. USA 76(6) 2720-2724 (1979); Schechter et al, Nature 278 835-838 (1979); Cole et al, Biol. Reprod. 12 516-521 (1975); Aston et al, J. Endocrinol. 110 381-388 (1986); Aston et al, Molec. Immunol. 24 143-150 (1987); Ferguson, Nature 174 411 (1954)). More specifically, Aston et al 1986, 1987 loc. cit. have shown that certain antibodies to growth hormones can enhance the biological activity of the hormone in vivo. It was concluded in these studies that enhancement of hormone by antibodies is characteristic of particular specificities, a property also described previously (Cole et al 1975 loc. cit.; Goodfriend et al 1970 loc. cit.). However, in none of these studies is a regime available to indicate how to generate reproducibly an enhancing antiserum by using a small peptide. EP-A-0137234 discloses that the large 7 kiloDalton fragment of growth hormone can produce antibodies that enhance growth hormone activity; however, this fragment may not always be suited for this purpose due to its size and its limited ability to produce a consistent enhancing antiserum. Currently, manufacture of such a large polypeptide may be problematic by peptide synthetic routes.
Enhancement of hormonal activity by the administration of a peptide fragment of GH has been disclosed in WO-A-8404915. In this particular disclosure it was shown that a short peptide derived from the amino terminal portion of the GH molecule potentiated hypoglycaemic activity; however this peptide was not administered in an immunogenic fashion. Both GH and insulin induce hypoglycaemia when administered to animals. The insulin-potentiating activity of peptide fragments of GH have also been described elsewhere (Pullin et al, Int. J. Peptide Protein Res. 18 318-323 (1981); Ng. et al, Diabetes 29 782-787 (1980)).
More recent contributions to the art have included the identification of various sequence fragments of natural growth hormones which, when made appropriately antigenic (for example by coupling them to a suitable carrier) have the capability of enhancing or potentiating the activity of endogenous or exogenous growth hormone. For example: WO-A-8807547 identifies the 35 to 53 region of natural growth hormones; WO-A-8901166 identi

REFERENCES:
Liberti, J.P.; Biochim. Biophys. Acta, vol. 675, 1981; pp. 239-247.
Chillemi, F., et al; Chemical Abstracts, vol. 89, 1978, p. 70; Abstract No. 71230.
Sato, K., et al; Chemical Abstracts, vol. 111, 1989, p. 80; Abstract No. 33758.
Aston, R., et al; Mol. Immunol., vol. 24, No. 2, 1987, pp. 143-150.
Borems et al, Biochemistry, vol. 26, pp. 7774-7778, (1987).
Poskus et al, Eur. J. Immunol., vol. 6, pp. 409-417 (1976).
Yamasaki et al, The Journal of Biol. Chem., vol. 247 (12), pp. 3874-3880, Jun. 25, 1972).
Goodfriend et al, J. Clin. Endocrinol. Outab., 30, pp. 565-572, (1970).
Shieh et al, Journal of Endocrinology, 145, pp. 169-174, (1995).

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