US 20070135335A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0135335 A1 Collier et al. (43) Pub. Date: Jun. 14, 2007 (54) THERAPEUTIC MOLECULES Related U.S. Application Data (75) Inventors: Greg Collier, Victoria (AU); Ken (60) Provisional application No. 60/446,191, filed on Feb. Walder, Victoria (AU); Lyndal 10, 2003. Kerr-Bayles, Victoria (AU) Publication Classification Correspondence Address: SCULLY, SCOTT, MURPHY & PRESSER, P.C. (51) Int. Cl. 4OO GARDEN CITY PLAZA A6II 38/17 (2006.01) SUTE 3OO A6IR 48/00 (2006.01) GARDEN CITY, NY 11530 (US) C07K I4/705 (2006.01) (52) U.S. Cl. ............................... 514/12: 514/44; 530/350 (73) Assignees: Autogen Research Pty Ltd., North Brighton, Victoria (AU); Deakin Univer (57) ABSTRACT sity, Waurn Ponds, Victoria (AU) The present invention relates generally to a ligand for a protein associated with modulating obesity, diabetes and (21) Appl. No.: 10/545,099 metabolic energy levels in animals including humans. More (22) PCT Fed: Feb. 10, 2004 particularly, the present invention provides a ligand of the protein, Beacon, and its homologs. The identification of a (86) PCT No.: PCT/AUO4/OO147 Beacon ligand permits the identification of agents which agonize or antagonize the Beacon-ligand interaction and, S 371(c)(1), hence, the development of therapeutic molecules useful in (2), (4) Date: May 4, 2006 modulating obesity, diabetes and/or energy imbalance. Patent Application Publication Jun. 14, 2007 Sheet 1 of 5 US 2007/0135335 A1 ?º?uOIO VIºInáH Patent Application Publication Jun. 14, 2007 Sheet 2 of 5 US 2007/0135335 A1 (II9.InáÃC)Iaun????9.InáH Patent Application Publication Jun. 14, 2007 Sheet 3 of 5 US 2007/0135335 A1 Patent Application Publication Jun. 14, 2007 Sheet 4 of 5 US 2007/0135335 A1 2 O 50 100 150 200 250 300 i Time (s) Figure 3A S. 800 2. 700 600 500 400 30 2 200 3 100 4. () O O 100 200 300 400 500 600 700 (s) Figure 3B O 5 100 150 200 250 300 (s) Figure 3C Patent Application Publication Jun. 14, 2007 Sheet 5 of 5 US 2007/0135335 A1 SO 100 150 200 250 300 (s) Figure 3D O 100 200 300 400 500 (s) Figure 3E O 120 240 360 480 600 (s) Figure 3F US 2007/01 35335 A1 Jun. 14, 2007 THERAPEUTIC MOLECULES 0008. In Australia, the recent AusLiab study estimated that 7.5 million Australians (60%) aged 25 years and over BACKGROUND OF THE INVENTION were overweight or obese. Of these, 2.6 million (21%) were 0001) 1. Field of the Invention obese (BMI>30) (Dunstan et al., Diabetes Res. Clin. Pract. 0002 The present invention relates generally to a ligand 57: 119-129, 2002). Similarly, the prevalence of obesity in for a protein associated with or which acts as a marker for the U.S. increased substantially between 1991 and 1998, conditions of inter alia a healthy or unhealthy state, includ increasing from 12% to 18% in Americans during this period ing the presence or absence of a disorder associated with (Mokdad et al., JAMA 282(16): 1519-1522, 1999). myopathy, obesity, anorexia, weight maintenance, diabetes, 0009. The high and increasing prevalence of obesity has disorders associated with mitochondrial dysfunction, serious health implications for both individuals and society genetic disorders, cancer, heart disease, inflammation, dis as a whole. Obesity is a complex and heterogeneous disorder orders associated with the immune system, infertility, dis and has been identified as a key risk indicator of preventable ease associated with the brain and/or metabolic energy morbidity and mortality. Obesity, for example, increases the levels. More particularly, the present invention is directed to risk of a number of other metabolic conditions including a ligand of the protein Beacon and its use or the interaction Type 2 diabetes mellitus and cardiovascular disease (Must et itself in therapeutic and diagnostic protocols for conditions al., JAMA 282(16): 1523-1529, 1999: Kopelman, Nature Such as inter alia a disorder associated with myopathy, 404: 635-643, 2000). Alongside obesity the prevalence of obesity, anorexia, weight maintenance, diabetes, disorders diabetes continues to increase rapidly. The AusLiab survey associated with mitochondrial dysfunction, genetic disor estimated that close to 1 million Australians aged 25 years ders, cancer, heart disease, inflammation, disorders associ and over have Type 2 diabetes (Dunstan et al., 2002 supra). ated with the immune system, infertility, disease associated This represents approximately 7.5% of the population. In the with the brain and/or metabolic energy levels. The Beacon U.S., the number of adults with diabetes increased by 49% ligand interaction is further useful as a target for the design between 1991 and 2000 (Marx, Science 686-689, 2002). It and/or identification of modulators of the activity and/or has been estimated that about 17 million people in the U.S. function of Beacon, its ligand or its interaction. The Subject have Type 2 diabetes and an equal number are thought to be ligand, therefore, is useful as a drug target or a target for pre-diabetic (Marx, 2002 supra). In Australia, the annual drug design or development. costs of obesity associated with diabetes and other disease 0003 2. Description of the Prior Art conditions has been conservatively estimated to be AUS S810 million for 1992-93 (National Health and Medical 0004 Bibliographic details of references provided in the Research Council, Acting on Australia's weight: A Strategy Subject specification are listed at the end of the specification. for the prevention of overweight and obesity. Canberra. 0005 Reference to any prior art in this specification is National Health and Medical Research Council, 1996). The not, and should not be taken as, an acknowledgment or any direct costs of diabetes and its complications in Australia in form of Suggestion that this prior art forms part of the 1993-94 were estimated at S681 million, or 2.2% of total common general knowledge in any country. health system costs in that year (Australian Institute of 0006 The increasing sophistication of recombinant DNA Health and Welfare (AIWH), Australia's Health, 2002, Can technology is greatly facilitating research and development berra: AIWH). in the medical, veterinary and allied human and animal 0010. A genetic basis for the etiology of obesity is health fields. This is particularly the case in the investigation indicated inter alia from Studies in twins, adoption studies of the genetic bases involved in the etiology of certain and population-based analyses which suggest that genetic disease conditions. One particularly significant condition effects account for 25-80% of the variation in body weight from the stand point of morbidity and mortality is obesity in the general population (Bouchard, 1994, Supra; Kopelman and its association with Type 2 diabetes and cardiovascular et al., Int. J. Obesity 18: 188-191, 1994; Ravussin, Metabo disease. lism 44(3): 12-14, 1995). It is considered that genes deter 0007 Obesity is defined as a pathological excess of body mine the possible range of body weight in an individual and fat and is the result of an imbalance between energy intake then the environment influences the point within this range and energy expenditure for a Sustained period of time. where the individual is located at any given time (Bouchard, Obesity is the most common metabolic disease found in 1994, Supra). However, despite numerous studies into genes affluent societies. The prevalence of obesity in these affluent thought to be involved in the pathogenesis of obesity, there Societies is alarmingly high, ranging from 10% to upwards have been Surprisingly few significant findings in this area. of 50% in some sub-populations (Bouchard, The genetics of In addition, genome-wide scans in various population Obesity, Boca Raton: CRC Press, 1994). Of particular groups have not produced definitive evidence of the chro concern is the fact that the prevalence of obesity appears to mosomal regions having a major effect on obesity. be rising consistently in affluent Societies and is now 0011) A number of tissues have been implicated in the increasing rapidly in less prosperous nations as they become pathophysiology of obesity and type 2 diabetes, and of more affluent and/or adopt cultural practices similar to those particular interest is the hypothalamus. The hypothalamus in more affluent countries (Zimmet, Diabetes Care 15: has long been recognized as a key brain area in the regula 232-252, 1992). The escalating rates of obesity globally tion of energy intake (Stellar, Psychol Rev 61: 5-22, 1954) have resulted in the World Health Organisation declaring an and it is now widely accepted that the hypothalamus plays obesity epidemic worldwide (World Trade Organisation. a central role in energy homeostasis, integrating and coor Obesity. Preventing and managing the global epidemic. dinating a large number of factors produced by and/or acting Report of a WHO Consultation on Obesity. Geneva: World on the hypothalamus. A number of these factors have been Health Organisation, 1998). investigated for their role in energy balance and body weight US 2007/01 35335 A1 Jun. 14, 2007 regulation, including neuropeptide Y, corticotropin-releas Diabetes 49: 1766-1771, 2000). Beacon treated animals ing hormone, melanin-concentrating hormone, leptin and revealed that the increase in body weight was a direct insulin. It has been proposed that genetic alterations per consequence of increased food intake as the treatment turbing the metabolic pathways regulating energy balance in affected neither the physical activity nor the energy expen the hypothalamus could contribute to the development of diture. The increase in body weight corresponded largely to obesity, and Subsequently diabetes. Thus, an important step an increase in fat content as the weight of the other organs in understanding the function of the hypothalamus in regu remained unchanged (Walder et al., Int.