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(12) Patent Application Publication (10) Pub. No.: US 2004/0142870 A1 Finn (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2004/0142870 A1 Finn (43) Pub US 2004O14287OA1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0142870 A1 Finn (43) Pub. Date: Jul. 22, 2004 (54) N-TERMINALLY MONOPEGYLATED (60) Provisional application No. 60/427.823, filed on Nov. HUMAN GROWTH HORMONE 20, 2002. CONJUGATES, PROCESS FOR THEIR PREPARATION, AND METHODS OF USE Publication Classification THEREOF (51) Int. Cl. ................................................. A61K 38/18 (76) Inventor: Rory F. Finn, Manchester, MO (US) (52) U.S. Cl. ................................................................ 514/12 Correspondence Address: PHARMACIA CORPORATION (57) ABSTRACT GLOBAL PATENT DEPARTMENT POST OFFICE BOX 1027 The present invention provides a chemically modified ST. LOUIS, MO 63006 (US) human Growth Hormone (hGH) prepared by attaching a polyethylene glycol butyraldehyde moiety to the N-terminal (21) Appl. No.: 10/771,895 phenylalanine of the protein. The chemically modified pro (22) Filed: Feb. 4, 2004 tein according to the present invention may have a much longer lasting hCGH activity than that of the un-modified Related U.S. Application Data hGH, enabling reduced dose and Scheduling opportunities. The present invention also includes methods of use for the (63) Continuation-in-part of application No. 10/718,340, treatment and/or prevention of diseases or disorders in filed on Nov. 20, 2003. which use of growth hormone is beneficial. Patent Application Publication Jul. 22, 2004 Sheet 1 of 6 US 2004/0142870 A1 TeIn6?H Á?ngM07 |-JL Patent Application Publication Jul. 22, 2004 Sheet 2 of 6 US 2004/0142870 A1 Figure 2 Phe Pro Thr Ile Pro Leu Ser Arg Lieu Phe Asp Asn 12 Ala Met Leu Arg Ala His Arg Lieu. His Glin Leu Ala 24 Phe Asp Thr Tyr Glin Glu Phe Glu Glu Ala Tyr Ile 36 Pro Lys Glu Glin Lys Tyr Ser Phe Leu Glin Asn Pro 48 Gln Thr Ser Lieu. Cys Phe Ser Glu Ser Ile Pro Thr 6 O Pro Ser Asn Arg Glu Glu Thr Glin Gln Lys Ser Asn 72 Leu Glu Lieu Leu Arg Ile Ser Leu Lleu Lieu. Ile Glin 84 Ser Trp Lieu Glu Pro Val Glin Ser Leu Arg Ser Val 96 Phe Ala Asn Ser Lieu Val Tyr Gly Ala Ser Asp Ser 108 Asn Val Tyr Asp Leu Lleu Lys Asp Lieu Glu Glu Gly 12 O Ile Glin Thr Lieu Met Gly Arg Leu Glu Asp Gly Ser 132 Pro Arg Thr Gly Glin Ile Phe Lys Glin Thr Tyr Ser 144 Lys Phe Asp Thr Asn Ser His Asn Asp Asp Ala Leu 156 Leu Lys Asn Tyr Gly Lieu Lleu Tyr Cys Phe Arg Lys 168 Asp Met Asp Llys Val Glu Thir Phe Leu Arg Ile Val 180 Glin Cys Arg Ser Val Glu Gly Ser Cys Gly Phe 191 SEQ ID NO: 1 Patent Application Publication Jul. 22, 2004 Sheet 5 of 6 US 2004/0142870 A1 5 CD C 2. O - -T - cy) CN O O) (uu) i5ue cy)eCL eféueav CY) CN Patent Application Publication Jul. 22, 2004 Sheet 6 of 6 US 2004/0142870 A1 Y4 O O. O. O. E E E E is Oc to (N. c. V. O. O. O. CO O V to o V OO GN N c as2 to 8 S. G9 o E H 9 St CN L CN V -T-- 3H o O O O O O O O O O O O C O O O O O N. o v Y. GN V v Iu/5u --O US 2004/O142870 A1 Jul. 22, 2004 N-TERMINALLY MONOPEGYLATED HUMAN tissues in older mammals. The organ Systems affected GROWTH HORMONE CONJUGATES, PROCESS include the skeleton, connective tissue, muscles, and Viscera FOR THEIR PREPARATION, AND METHODS OF Such as liver, intestine, and kidneyS. Growth hormones exert USE THEREOF their effect through interaction with Specific receptors on the target cell's membrane. hCGH is a member of a family of 0001. The present application is a continuation in part of homologous hormones that include placental lactogens, pro U.S. application Ser. No. 10/718340 filed Nov. 20, 2003, lactins, and other genetic and Species variants or growth which itself claims priority under Title 35, United States hormone (Nicoll, C. S., et al. (1986) Endocrine Reviews 7: Code, S119 to U.S. Provisional application Serial No. 169). hCGH is unusual among these in that it exhibits broad 60/427.823, filed Nov. 20, 2002, which are incorporated by Species Specificity and binds to either the cloned Somatoge reference in their entirety as if written herein. nic (Leung, D. W., et al. 1987 Nature 330; 537) or prolactin receptor (Boutin, J. M., et al. 1988Cell, 53: 69). The FIELD OF THE INVENTION cloned gene for hCGH has been expressed in a Secreted form 0002 The present invention relates to a chemical modi in Escherichia coli (Chang, C. N., et al. 1987Gene fication, including PEGylation, of human Growth Hormone 55:189), and its DNA and amino acid sequence has been (hGH) and agonist variants thereof by which the chemical reported (Goeddel, et al. 1979)Nature 281: 544; Gray, et al. and/or physiological properties of hCGH can be changed. The 1985 Gene 39:247). PEGylated hCGH may have an increased plasma residency duration, decreased clearance rate, improved Stability, 0006 Human growth hormone (hGH) participates in decreased antigenicity, decreased PEGylation heterogeneity much of the regulation of normal human growth and devel or a combination thereof. The present invention also relates opment. This pituitary hormone exhibits a multitude of to processes for the modification of hCGH. In addition, the biological effects including linear growth (Somatogenesis), present invention relates to pharmaceutical compositions lactation, activation of macrophages, insulin-like and dia comprising the modified hCGH. A further embodiment is the betogenic effects among others (Chawla, R, K. (1983) Ann. use of the modified hCGH for the treatment of growth and Rev. Med. 34,519; Edwards, C. K. et al. (1988) Science 239, development disorders. 769; Thomer, M. O., et al. (1988) J. Clin. Invest. 81:745). Growth hormone deficiency in children leads to dwarfism, BACKGROUND OF THE INVENTION which has been Successfully treated for more than a decade by exogenous administration of hCGH. 0003) Human growth hormone (hGH) is a protein com prising a single chain of 191 amino acids croSS-linked by 0007. In adults, as well as in children, hCGH maintains a two disulphide bridges and the monomeric form has a normal body composition by increasing nitrogen retention molecular weight of 22 kDa. Human GH is secreted by the and Stimulation of Skeletal muscle growth, and by mobili pituitary gland and which also can be produced by recom Zation of body fat. Visceral adipose tissue is particularly binant genetic engineering. hCGH will cause growth in all responsive to hCGH. In addition to enhanced lipolysis, hCGH bodily tissues that are capable of growth. hCGH playS an decreases the uptake of triglycerides into body fat Stores. important role not only in promoting growth in the growing Serum concentrations of IGF-I (insulin-like growth factor phase in human beings but also in maintaining normal body I), and IGFBP3 (insulin-like growth factor binding protein composition, anabolism, and lipid metabolism (K. Barneis. 3) are increased by hCGH. And U. Keller, Baillieres Clin. Endocrinlo. Metab. 10:337 0008 Human growth hormone (hGH) is a single-chain (1996)). polypeptide consisting of 191 amino acids (molecular 0004 Recombinant hCGH has been commercially avail weight 21,500). Disulfide bonds link positions 53 and 165 able for Several years. Two types of therapeutically useful and positions 182 and 189. Niall, Nature, New Biology, recombinant hCGH preparations are present on the market: 230:90 (1971). hCGH is a potent anabolic agent, especially the authentic one, e.g. GenotropinTM, or NutropinTM and an due to retention of nitrogen, phosphorus, potassium, and analogue with an additional methionine residue at the N-ter calcium. Treatment of hypophySectomized rats with GH can minal end, e.g. SomatonormTM. hCGH is used to stimulate restore at least a portion of the growth rate of the rats. Moore linear growth in patients with hypo pituitary dwarfism also et al., Endocrinology 122:2920-2926 (1988). Among its referred to as Growth Hormone Deficiency (GHD) or Turn most striking effects in hypo pituitary (GH-deficient) Sub er's Syndrome but other indications have also been Sug jects is accelerated linear growth of bone-growth-plate gested including long-term treatment of growth failure in cartilage resulting in increased Stature. Kaplan, Growth children who were born short for gestational age (SGA), for Disorders in Children and Adolescents (Springfield, Ill.: treatment of patients with Prader-Willi syndrome (PWS), Charles C. Thomas, 1964). chronic renal insufficiency (CRI), Aids wasting, and Aging. 0009 hCGH causes a variety of physiological and meta Adult GH deficiency (aCHD) patients have various prob bolic effects in various animal models including linear bone lems, Such as characteristic changes in body composition growth, lactation, activation of macrophages, insulin-like including increase in fat mass, decrease in lean body mass and diabetogenic effects, and others (R. K. Chawla et al., and extracellular fluid, and reduction of bone mineral den Annu. Rev. Med. 34:519 (1983); O. G. P. Isaksson et al., sity, metabolic abnormalities of lipids, and cardiovascular Annu. Rev. Physiol. 47, 483 (1985); C. K. Edwards et al., dysfunction. Many of those problems are improved by hCGH Science 239, 769 (1988); M. O. Thomer and M. L. Vance, J. replacement therapy (J. Verhelst J and R. Abs. Clin. Invest.82:745 (1988); J. P. Hughes and H. G. Friesen, Drugs.;62:2399 (2002). Ann. Rev. Physiol. 47:469 (1985)). It has been reported that, 0005. A major biological effect of growth hormone (GH) especially in women after menopause, GH Secretion is to promote growth in young mammals and maintenance of declines with age.
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