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I WO 2U11/1 16432 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date i 29 September 2011 (29.09.2011) WOk 2U1 1/1 16432 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every CI2Q 1/68 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/AU201 1/000349 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 28 March 201 1 (28.03.201 1) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 2010901300 26 March 2010 (26.03.2010) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): BOND GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, UNIVERSITY LTD [AU/AU]; Bond University, Gold ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Coast, Queensland 4229 (AU). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors; and LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (75) Inventors/ Applicants (for US only): MARSHALL- SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GRADISNIK, Sonya Maree [AU/AU]; 54 Harwood GW, ML, MR, NE, SN, TD, TG). Road, Burringbar, New South Wales 2483 (AU). GRAY, Bon [AU/AU]; 218 Woodlands Drive, Thornlands, Published: Queensland 4164 (AU). TAJOURI, Lotti [FR/AU]; 100 — with international search report (Art. 21(3)) Henry Cotton Drive, Parkwood, Queensland 4214 (AU). (74) Agent: PIZZEYS PATENT & TRADE MARK AT¬ TORNEYS; Level 20, 324 Queen Street, (GPO Box 1374), Brisbane, QLD 4000 (AU). (54) Title: METHODS AND COMPOSITIONS FOR DETECTING BANNED SUBSTANCES (57) Abstract: The present invention relates to methods and compositions thereof for detecting banned substances and doping agents. The present invention further relates to measurement of gene expression to detect doping events such as the use of recom binant human Growth Hormone (rhGH). Methods for Detection of Doping and Compositions Thereof Field of the Invention The present invention relates to methods and compositions thereof for detecting substances administered to the body. The present invention further relates to measurements of gene expression to detect doping events such as the delivery of a prohibited exogenous substance like recombinant human growth hormone (rhGH) into the body. Background It is thought that many substances such as growth hormone (GH) and in particular rhGH have been ubiquitously used by professional athletes predominantly since about the early to mid 1980s to enhance their athletic performance (McHugh et al., 2005). However, such a substance has been banned for many, many years. rhGH is an "officially" banned substance as it is present on the World Anti-Doping Agency list of banned agents/substances. Two actions of GH are considered beneficial to athletes and their performance. One is anabolic and the other lipolytic. The effects are (i) an increase in lean body mass and (ii) a reduction in fat mass. In regards to the anabolic component of GH, some of the action is mediated via the production of insulin-like growth factor-l (IGF-I). The regulation of protein synthesis involves the synergistic actions of GH and IGF-I stimulating protein synthesis. It has been found that GH stimulates protein synthesis via a mechanism that is different to the mechanism triggered by anabolic steroids and therefore it seems likely that their effects if taken together will be at least additive if not synergistic. This has resulted in numerous athletes combining at least GH and anabolic steroids and possibly insulin as well (Sonksen, 2001). It is estimated that GH doses used by athletes are about up to 10 times higher than those used by endocrinologists in treating various growth-related disorders or abnormalities. It is evident that athletes that take such a high dose are putting themselves at risk of contracting various conditions such as hypertension, diabetes and Creutzfeldt-Jakob disease. In the anti-doping community, the detection of GH is by far the greatest modern challenge today. The detection of GH abuse has proved difficult for many reasons. Unlike many abused substances, e.g. synthetic anabolic steroids, GH is a naturally occurring protein in the body. As such, a method of detecting GH doping must be able to identify levels of GH that are above normal physiological levels of GH while excluding pathological conditions that involve high levels of GH such as acromegaly. Further, the detection of GH is a "moving target" as routine exercise and stress are predominant stimulators of GH production (Prinz et al., 1983; Savine and Sonksen, 2000). Consequently, natural GH concentrations are often at their highest in the immediate post-competition setting when most drug testing occurs. However, recombinant human GH is almost identical to pituitary GH. Cadaveric GH, which can purchased on-line, is indistinguishable to endogenously produced GH. Less than 0.1% of GH and IGF-I is excreted and even that is erratic, thus rendering urine testing unreliable and unfeasible (Moreira-Andres et al., 1993). Endogenously secreted GH has a half-life of approximately 13 min (Sohmiya and Kato, 1992) which is expeditiously cleared from the body by such organs as the liver and the kidney but also by peripheral tissues. Recombinant human GH (rhGH) has a similar half-life as endogenously secreted GH if rhGH is intravenously administered (Refetoff and Sonksen, 1970; Haffner et al., 1994). However, the preferred route of administration of exogenous GH is via daily, subcutaneous injection. Following injection, plasma GH concentrations increase and reach a maximum concentration after about 2-6 hours (Kearns et al., 1991; Janssen et al., 1999). Soon thereafter, rhGH is quickly cleared from the body. In fact, GH is routinely undetectable in women 12 hours after injection, whilst men have only low levels of GH. (Giannoulis et al., 2005). There are two current methods for detection of GH doping which are World Anti-Doping Agency (WADA)-approved blood tests. One is predicated on the detection of different pituitary GH isoforms, whilst the second method involves measurement of GH-dependent markers. In the first method, it is acknowledged that GH exists as multiple isoforms; 70% of circulating GH is in the form of a 22-kilo Dalton (kDa) polypeptide, whereas 5-10% occurs as a 20 kDa isoform due to mRNA splicing. It is also acknowledged that dimers and oligomers of GH exist as well as acidic, desaminated, acylated and fragmented forms (Baumann, 1999). This method is predicated on the theory that endogenous GH occurs as a number of isoforms whilst, in contrast, rhGH contains only the 22 kDa isoform. It has been found that a suppression of endogenous GH secretion through negative feedback to the pituitary occurs when rhGH is administered in sufficiently high doses. In effect, the ratio between 22 kDa GH and non-22 kDa GH increases (Bidlingmaier et al., 2003). The second method concerns the specific measurement of either the 22 or 20 kDa GH (Momomura et al., 2000) which is predicated on the principle that the ratio between 22 kDa and total GH is less than 1 with a normal distribution of values, whereas individuals receiving GH have values that are greater than one (Wu et al., 1999). However, it has been found that exercise causes a transient relative increase in the 22 kDa isoform, thereby lowering the sensitivity of the test if samples are taken immediately after competition (Wallace et al., 2001a, b). It is known that the half-life of rhGH is short and the clearance is quick when injected subcutaneously but even shorter and quicker when injected intravenously. As such, the time frame of detecting GH doping is approximately less than 36 hours after last administration of exogenous GH (Keller et al., 2007). Since GH is usually administered in the evening, GH is often undetectable in a blood sample obtained the following day (Giannoulis et al., 2005). In women, the 20 kDa GH remains suppressed for approximately 14-30 hours whilst in men, 20 kDa GH remains undetectable for up to 36 hours (Keller et al., 2007). Spontaneous GH secretion, such as secretion of the 20 kDa GH, returns 48 hours subsequent to the last dose of rhGH administration (Wu et al., 1990). As a consequence, any athlete who terminates administration of GH at least two days prior to a competition will not be detected. Taken together, neither of the two methods described above would likely detect doping with exogenous GH e.g. rhGH in a classical 'post competition' dope testing scenario. The only scenario that may yield results from the two methods described above is via unannounced 'out of competition' testing which is inconvenient and insufficient. In light of the above, it is apparent that a long, felt need as existed for a method that detects doping with exogenous GH when last administration was at least several days if not weeks before competition.
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