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WO 2016/176656 A2 3 November 2016 (03.11.2016) P O P C T

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WO 2016/176656 A2 3 November 2016 (03.11.2016) P O P C T (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 WO 2016/176656 A2 3 November 2016 (03.11.2016) P O P C T (51) International Patent Classification: (74) Agent: BELLOWS, Brent, R.; Knowles Intellectual Prop A61K 39/00 (2006.01) erty Strategies, LLC, 400 Perimeter Center Terrace NE, Suite 200, Atlanta, GA 30346 (US). (21) International Application Number: PCT/US20 16/030303 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 29 April 2016 (29.04.2016) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) Filing Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (26) Publication Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (30) Priority Data: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 62/155,217 30 April 2015 (30.04.2015) US PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/232,148 24 September 2015 (24.09.2015) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/268,257 16 December 201 5 (16. 12.2015) us TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicants: PRESIDENT AND FELLOWS OF HAR¬ (84) Designated States (unless otherwise indicated, for every VARD COLLEGE [US/US]; 17 Quincy Street, Cam kind of regional protection available): ARIPO (BW, GH, bridge, MA 021 38 (US). UCB BIOPHARMA SPRL GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, [BE/BE]; 60, allee de la Recherche, B-1070 Brussels (BE). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: HOTAMISLIGIL, Gokhan, S.; 26 Halsey DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Ave., Wellesley, MA 02482 (US). BURAK, Mehmet, F.; LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 90 Belmont St., Watertown, MA 02472 (US). ENGIN, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Feyza; 420 W. Dayton St., #417, Madison, WI 53703 GW, KM, ML, MR, NE, SN, TD, TG). (US). WIDENMAIER, Scott, B.; 9 1 Claymoss Rd., Declarations under Rule 4.17 : Brighton, MA 02135 (US). ROBERTS, Elisabeth, Helen; c/o IPD, UCB Celltech, 208 Bath Road, Slough, Berkshire — as to applicant's entitlement to applyfor and be granted a Sl l 3 E (GB). MOORE, Adrian, Richard; c/o IPD, patent (Rule 4.1 7(H)) UCB Celltech, 208 Bath Road, Slough, Berkshire Sl l — as to the applicant's entitlement to claim the priority of the 3 E (GB). DOYLE, Carl, Brendan; c/o IPD, UCB Cell earlier application (Rule 4.1 7(in)) tech, 208 Bath Road, Slough, Berkshire Sl l 3WE (GB). ADAMS, Ralph; c/o IPD, UCB Celltech, 208 Bath Road, Published: Slough, Berkshire Sl l 3WE (GB). HERVE, Karine, — without international search report and to be republished Jeannine Madeleine; 3565 Flat A, West 3rd Avenue, Van upon receipt of that report (Rule 48.2(g)) couver, British Columbia V6R 1L8 (CA). WALES, Shauna, Mhairi; c/o IPD, UCB Celltech, 208 Bath Road, — with sequence listingpart of description (Rule 5.2(a)) Slough, Berkshire Sl l 3WE (GB). TYSON, Kerry, Louise; c/o IPD, UCB Celltech, 208 Bath Road, Slough, Berkshire Sl l 3WE (GB). < (54) Title: ANTI-AP2 ANTIBODIES AND ANTIGEN BINDING AGENTS TO TREAT METABOLIC DISORDERS (57) Abstract: This invention is in the area of improved anti-aP2 antibodies and antigen binding agents, and compositions thereof, v which target the lipid chaperone aP2/FABP4 (referred to as "aP2") for use in treating disorders such as diabetes, obesity, cardiovas - o cular disease, fatty liver disease, and/or cancer, among others. In one aspect, improved treatments for aP2 mediated disorders are dis - closed in which serum aP2 is targeted and the biological activity of aP2 is neutralized or modulated using low-binding affinity aP2 monoclonal antibodies, providing lower fasting blood glucose levels, improved systemic glucose metabolism, increased systemic in o sulin sensitivity, reduced fat mass, reduced liver steatosis, reduced cardiovascular disease and/or a reduced risk of developing cardi - ovascular disease. ANTI-AP2 ANTIBODIES AND ANTIGEN BINDING AGENTS T O TREAT METABOLIC DISORDERS RELATED APPLICATIONS This application is related to and claims the benefit of provisional U.S. Application No. 62/155,217, filed April 30, 2015, provisional U.S. Application No. 62/232,148, filed September 24, 2015, and provisional U.S. Application No. 62/268,257, filed December 16, 2015. The entirety of these provisional applications are hereby incorporated by reference for all purposes. FIELD OF THE INVENTION This invention is in the area of improved anti-aP2 antibodies and antigen binding agents, and compositions thereof, which target the lipid chaperone aP2/FABP4 (referred to as "aP2") for use in treating disorders such as diabetes, obesity, cardiovascular disease, fatty liver disease, and/or cancer, among others. In one aspect, improved treatments for aP2 mediated disorders are disclosed in which serum aP2 is targeted and the biological activity of aP2 is neutralized or modulated using low-binding affinity aP2 monoclonal antibodies, providing lower fasting blood glucose levels, improved systemic glucose metabolism, increased systemic insulin sensitivity, reduced fat mass, reduced liver steatosis, reduced cardiovascular disease and/or a reduced risk of developing cardiovascular disease. INCORPORATION BY REFERENCE The contents of the text file named "15020-001USlSequenceListing_ST25updated.txt" which was created on April 25, 2016 and is 258 KB in size, are hereby incorporated by reference in their entirety. Human adipocyte lipid-binding protein (aP2) belongs to a family of intracellular lipid- binding proteins involved in the transport and storage of lipids (Banzszak et a ., (1994) Adv. Protein Chem. 45, 89-151). The aP2 protein is involved in lipolysis and lipogenesis and has been indicated in diseases of lipid and energy metabolism such as diabetes, atherosclerosis, and metabolic syndromes. aP2 has also been indicated in the integration of metabolic and inflammatory response systems. (Ozcan et al., (2006) Science 313(5790):! 137-40; Makowski et al., (2005) J Biol Chem. 280(13): 12888-95; and Erbay et al., (2009) Nat Med. 15(12): 1383-91). More recently, aP2 has been shown to be differentially expressed in certain soft tissue tumors such as certain liposarcomas (Kashima et al, (2013) Virchows Arch 462, 465-472). aP2 is highly expressed in adipocytes and regulated by peroxisome-proliferator-activated receptor- γ (PPARy) agonists, insulin, and fatty acids (Hertzel et al., (2000) Trends Endocri ol Metab. 11, 175-180; Hunt et al, (1986) PNAS USA 83, 3786-3790; Melki et al., (1993) J . Lipid Res. 34, 1527-1534; Distel et al, (1992) J . Biol. Chem 267, 5937-5941). Studies in aP2 deficient mice (aP2-/-) indicate protection against the development of insulin resistance associated with genetic or diet-induced obesity and improved lipid profile in adipose tissue with increased levels of C16:ln7-palmitoleate, reduced hepatosteatosis, and improved control of hepatic glucose production and peripheral glucose disposal (Hotamisligil et al., (1996) Science 274, 1377-1379; Uysal et al., (2000) Endocrinol. 141, 3388-3396; Cao et al., (2008) Cell 134, 933-944). In addition, genetic deficiency or pharmacological blockade of aP2 reduces both early and advanced atherosclerotic lesions in the apoiipoprotein E-deficient (ApoE-/-) mouse model (Furuhashi et al., (2007) Nature, Jun 21;447(7147):959-65; Makowski et al., (2001) Nature Med. 7, 699-705; Layne et al, (2001) FASEB 15, 2733-2735; Boord et al., (2002) Arteriosclerosis, Thrombosis, and Vas. Bio. 22, 1686-1691). Furthermore, aP2-deficiency leads to a marked protection against early and advanced atherosclerosis in apoiipoprotein E-deficient (ApoE-/-) mice (Makowski et al., (2001) Nature Med. 7, 699-705; Fu et al., (2000) J . Lipid Res. 41, 2017- 2023) Hence, aP2 plays a critical role in many aspects of development of metabolic disease in preclinical models. In the past two decades, the biological functions of FABPs in general and aP2 in particular have primarily been attributed to their action as intracellular proteins. Since the abundance of aP2 protein in the adipocytes is extremely high, accounting for up to few percent of the total cellular protein (Cao et al., (2013) Cell Metab. 17(5):768-78), therapeutically targeting aP2 with traditional approaches has been challenging, and the promising success obtained in preclinical models (Furuhashi et al., (2007) Nature 447, 959-965; Won et al , (2014) Nature Mat. 13, 157-1 164; Cai et al., (2013) Acta Pharm. Sinica 34, 1397-1402; Hoo et al., (2013) J of Hepat. 58, 358-364) has been slow to progress toward clinical translation. In addition to its presence in the cytoplasm, it has recently been shown that aP2 is actively secreted from adipose tissue through a non-classical regulated pathway (Cao et al , (2013) Cell Metab. 17(5), 768-778; Ertunc et al., (2015) J . Lipid Res. 56, 423-424). The secreted form of aP2 acts as a novel adipokine and regulates hepatic glucose production and systemic glucose homeostasis i mice in response to fasting and fasting-related signals. Serum aP2 levels are significantly elevated in obese mice, and blocking circulating aP2 improves glucose homeostasis in mice with diet-induced obesity (Cao et al., (2013) Cell Metab. 17(5):768-78).
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