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WO 2007/056812 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 24 May 2007 (24.05.2007) PCT WO 2007/056812 Al (51) International Patent Classification: Victoria 3941 (AU). WHITTAKER, Jason, S. [AU/AU]; C07K 14/54 (2006.01) C07H 21/04 (2006.01) 24 Maddison Street, Redfern East, New South Wales A61K 38/19 (2006.01) C07K 14/52 (2006.01) 2016 (AU). DOMAGALA, Teresa, A. [AU/AU]; 14/30 A61K 38/20 (2006.01) C07K 14/61 (2006.01) Garden Street, Alexandria, New South Wales 2015 (AU). A61K 38/27 (2006.01) C07K 14/715 (2006.01) SIMPSON, Raina, J. [AU/AU]; 10 Snowgum Street, A61P 7/00 (2006.01) C07 /4/72 (2006.01) Acacia Gardens, New South Wales 2763 (AU). A61P 35/00 (2006.01) C07K 19/00 (2006.01) A61P 37/00 (2006.01) GOlN 33/543 (2006.01) (74) Agents: HUGHES, John, E., L. et al.; DAVIES COLLI- C07H 21/02 (2006.01) SON CAVE, 1Nicholson Street, Melbourne, Victoria 3000 (AU). (21) International Application Number: PCT/AU2006/001718 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, 16 November 2006 (16.1 1.2006) CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, (25) Filing Language: English JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MY, (26) Publication Language: English MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, (30) Priority Data: RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW 60/737,385 16 November 2005 (16.1 1.2005) US 2005906599 25 November 2005 (25.1 1.2005) AU (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): APOLLO kind of regional protection available): ARIPO (BW, GH, LIFE SCIENCES LIMITED [AU/AU]; Level 1, 147 GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, Queen Street, Beaconsfield, New South Wales 2015 (AU). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (72) Inventors; and FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, (75) Inventors/Applicants (for US only): PRIEST, John, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, D. [AU/AU]; 12b Grafton Street, Balmain, New South GN, GQ, GW, ML, MR, NE, SN, TD, TG). Wales 2041 (AU). WATTS, Alan, D. [AU/AU]; 3 1 Un- dercliffe Street, Dee Why, New South Wales 2099 (AU). Published: THOMAS, Nikolien, S. [AU/JP]; #608 Mansion Freebell, — with international search report 2-10 Ushijima-cho, Nishi-ku, Nagoya, Aichi 451-0046 (JP). LIDDELL, Catherine, A. [AU/AU]; 6 Caroline For two-letter codes and other abbreviations, refer to the "G uid Street, Kingsgrove, New South Wales 2208 (AU). PILK- ance Notes on Codes and Abbreviations" appearing at the beg in INGTON, Glenn, R. [AU/AU]; 6 Allara Street, Rye, ning of each regular issue of the PCT Gazette. (54) Title: A MOLECULE AND CHIMERIC MOLECULES THEREOF (57) Abstract: The present invention relates generally to the fields of proteins, diagnostics, therapeutics and nutrition. More par- ticularly, the present invention provides an isolated protein molecule that comprises a cytokine family receptor protein, such as IL-I receptor alpha subunit (IL-IRa), IL-3 receptor alpha subunit (IL-3Ra), IL-7 receptor alpha subunit (IL-7Ra), growth hormone recep- tor (GHR) or a ligand thereof, such as IL-I receptor antagonist (I1-1RA) or chimeric molecules thereof comprising at least a portion of the protein molecule, such as IL-IRa-Fc, IL-3Ra-Fc, IL-7Ra-Fc, GHR-Fc, IL-IRA-Fc; wherein the protein or chimeric molecule thereof has a profile of measurable physiochemical parameters, wherein the profile is indicative of, associated with or forms the basis of one or more pharmacological traits. The present invention further contemplates the use of the isolated protein or chimeric molecule thereof in a range of diagnostic, prophylactic, therapeutic, nutritional and/or research applications. A MOLECULE AND CHIMERIC MOLECULES THEREOF BACKGROUND OF THE INVENTION FIELD OF THE INVENTION The present invention relates generally to the fields of proteins, diagnostics, therapeutics and nutrition. More particularly, the present invention provides an isolated protein molecule that comprises a cytokine family receptor protein, such as IL-I receptor alpha subunit (IL-IRa), IL-3 receptor alpha subunit (IL-3Ra), IL-7 receptor alpha subunit (IL- 7Ra), growth hormone receptor (GHR) or a ligand thereof, such as IL-I receptor antagonist (II-IRA) or chimeric molecules thereof comprising at least a portion of the protein molecule, such as IL-IRa-Fc, IL-3Ra-Fc, IL-7Ra-Fc, GHR-Fc, IL-IRA-Fc; wherein the protein or chimeric molecule thereof has a profile of measurable physiochemical parameters, wherein the profile is indicative of, associated with or forms the basis of one or more pharmacological traits. The present invention further contemplates the use of the isolated protein or chimeric molecule thereof in a range of diagnostic, prophylactic, therapeutic, nutritional and/or research applications. DESCRIPTION OF THE PRIOR ART Reference to any prior art in this specification is not, and should not be taken as an acknowledgment or any form of suggestion that this prior art forms a part of the common general knowledge. Interleukins are pleotropic molecules that regulate immune responses, inflammation, hematopoiesis as well as oncogenesis. The actions of class I interleukins include regulating the survival, proliferation and differentiation of immune cells including B and T lymphocytes, macrophages, cytotoxic T cells, neutrophils, dendritic cells, natural killer cells, eosinophils, basophils, mast cells, megakaryocytes and erythroid cells. The effects of interleukins are exerted through cytokine receptors. These cytokine receptors may be classified as class I and class II. The class I cytokine receptors include receptors for IL-3, IL-4, IL-6, IL-5, IL-7 and human growth hormone (hGH). Structurally, these receptors share structural domains in the extracellular region including fibronectin type III domains, conserved amino acid sequence motifs for four conserved cysteine residues and a conserved sequence of Trp-Ser-X-Trp-Ser. The majority of these receptors consist of two polypeptide chains, namely a cytokine- specific subunit and a signal-transducing subunit and the receptors are further classified according to their signal transducing subunit as follows; receptors for IL-3, IL-5 share the common signal transducing β subunit; the receptors for IL-4 and IL-7 share the common gamma chain and receptor for IL-6 the gpl30 subunit. Many disease states result from deregulated class I interleukin signalling particularly inflammatory and malignant diseases. Inhibitors that competitively inhibit deregulated interleukin signalling of membrane bound receptors would be beneficial in the treatment of these disease states. These inhibitors would comprise soluble cytokine receptor extra cellular domains such as IL-3R, IL-7R, and hGHR fused to the Fc region of the human IgG. Additionally, IL-I signalling can be inhibited by IL-I receptor antagonist (IL-IRA) as well as IL-I receptor alpha (IL-IRa) or chimeric molecules thereof. The biological effector functions exerted by the cytokine receptor family proteins as well as their respective ligands or receptors may have significant potential as therapeutic agents to modulate physiological processes. However, minor changes to the molecule such as primary, secondary, tertiary or quaternary structure and co- or post-translational modification patterns can have a significant impact on the activity, secretion, antigenicty and clearance of the protein. It is possible, therefore, that the proteins can be generated with specific primary, secondary, tertiary or quaternary structure, or co- or post- translational structure or make-up that confer unique or particularly useful properties. There is consequently a need to evaluate the physiochemical properties of proteins under different conditions of production to determine whether they have useful physiochemical characteristics or other pharmacological traits. The problem to date is that production of commercially available proteins are carried out in cells derived from species that are evolutionary distant to humans, cells such as bacteria, yeast, fungi, and insect. These cells express proteins that either lack glycosylation or exhibit glycosylation repertoires that are distinct to human cells and this impacts substantially on their clinical utility. For example, proteins expressed in yeast or fungi systems such as Aspergillus possess a high density of mannose which makes the protein therapeutically useless (Herscovics et al FASEB J 7:540-550, 1993). Even in non-human mammalian expression systems such as Chinese hamster ovary (CHO) cells, significant differences in the glycosylation patterns are documented compared with that of human cells. For example, most mammals, including rodents, express the enzyme (α 1,3) galactotransferase, which generates Gal (α 1,3)-Gal (β l,4)-GlcNAc oligosaccharides on glycoproteins. However in humans, apes and Old World monkeys, the expression of this enzyme has become inactivated through a frameshift mutation in the gene. (Larsen et al. J Biol Chem 265:7055-7061, 1990) Although most of the CHO cell lines used for recombinant protein synthesis, such as Dux-Bll, have inactivated the gene expressing (α 1,3) Galactotransferase, they still lack a functional (α 2, 6) sialyltransferase enzyme for synthesis of (α 2, 6)-linked terminal sialic acids which are present in human cells.
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