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Wo 2011/133948 A2 (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 27 October 2011 (27.10.2011) WO 2011/133948 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 38/22 (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/US201 1/033684 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, JL, IN, IS, JP, KE, KG, KM, KN, KP, 22 April 201 1 (22.04.201 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 Langi 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: 61/327,098 22 April 2010 (22.04.2010) US (84) Designated States (unless otherwise indicated, for every 61/364,359 14 July 2010 (14.07.2010) US kind of regional protection available): ARIPO (BW, GH, 61/405,560 2 1 October 2010 (21 .10.2010) us GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 61/445,468 22 February 201 1 (22.02.201 1) us ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (71) Applicant (for all designated States except US): EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LONGEVITY BIOTECH, INC. [US/US]; 3624 Market LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Street, Suite 300, Philadelphia, PA 19104 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and (75) Inventors/ Applicants (for US only): SHANDLER, Published: Scott, J. [US/US]; 2303 Delancey Place, Apartment #2, — without international search report and to be republished Philadelphia, PA 19103 (US). GELLMAN, Samuel, H. upon receipt of that report (Rule 48.2(g)) [US/US]; 222 Glacier Drive, Madison, WI 53705 (US). (74) Agent: ZURAWSKI, John, A.; Pepper Hamilton LLP, 899 Cassatt Road, Berwyn, PA 193 12 (US). < (54) Title: HIGHLY ACTIVE POLYPEPTIDES AND METHODS OF MAKING AND USING THE SAME (57) Abstract: This invention relates to novel compositions comprising analogs of naturally occurring polypeptides, wherein the analog comprises an a-amino acid and at least one β- amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways. The composi- tions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity ¾ with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived. HIGHLY ACTIVE POLYPEPTIDES AND METHODS OF MAKING AND USING THE SAME CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Serial Number 61/327,098, filed on April 22, 2010; U.S. Provisional Serial Number 61/364,359, filed on July 14, 2010; U.S. Provisional Serial Number 61/405,560, filed on October 21, 2010; and U.S. Provisional Serial Number 61/445,468, filed on February 22, 20 , all of which are herein incorporated by reference in their entirety. FIELD OF THE INVENTION The invention relates generally to compositions comprising modified polypeptide sequences with greater resistance to degradation and equivalent and or increased bioactivity as compared to naturally encoded, unmodified polypeptide sequences, and to methods of making the compositions and methods of using the compositions as pharmaceutically active agents to treat disease in animals, including humans. BACKGROUND OF THE INVENTION The secretin family is a family of well-conserved animal proteins with a variety of biological functions. Biologically active members of the secretin family are generally from about 26 to about 65 amino acids in length and are thought to have relatively simple alpha- helical secondary structures. Many members are originally produced in vivo as larger pro¬ peptides, which are eventually converted in the active forms. Members of the secretin family include the following proteins: GHRF, GIP, GLP-1, Glucagon, PACAP-27, PACAP-38, PHM, PrP, and secretin. The q25 region of chromosome 6 on the human genome encodes another secretin family member that is 170 amino acids long which becomes post- translationally cleaved to form vasoactive intestinal peptide (VIP). The active form of the VIP polypeptide is a 28 amino acid protein that functions, among other ways, to reduce arterial blood pressure, to increase vasodilation of blood vessel walls, to relax smooth muscle in the respiratory system and gastrointestinal tissues reduce inflammatory responses through both promotion of Th2 differentiation as well as the reduction of Thl responses, modulate both the innate and adaptive immune response, and to stimulate secretion of electrolytes in the gut. VIP has also been shown to be active in the central nervous system as a neurotransmitter and in communication with lymphocytes. Bioactivity of VIP is transmuted through three known receptor subtypes: VIPiR, VIP2R, and PACiR. These receptors are known to induce cAMP concentration as well as stimulate the production of intracellular calcium. Their affinities for secretins such as VIP vary depending upon the subtype and the amino acid sequence of the ligand. Secretin family members have short half-lives. For instance, VIP has a half-life of about two minutes in the blood stream. It is desirable to identify polypeptides that mimic the function of secretins such as VIP, but have increased half-life and equivalent or more bioactivity than the naturally occurring VIP amino acid sequence. It is also desirable to identify another peptidomimetic of VIP to have association to one receptor subtype over another secretin receptor. HDL cholesterol level is inversely related to the incidence of coronary heart disease and recently received increasing attention as a novel target in lipid management of treating atherosclerotic vascular disease. Direct vascular protective effects of HDL have been attributed to apolipoprotein (apo) A- or apoA-I-associated molecules in HDL using direct intravenous injections of homologous HDL,3 recombinant mutant apoA-Imilano or apoA-I gene therapy, or use of transgenic animals overexpressing apoA-I or apoAl-re!ated molecules such as paraoxonase. A recent phase II randomized trial showed that 5 weekly intravenous injections of recombinant apoA-lmilano induced rapid regression of coronary atherosclerotic lesions in humans. It is desirable to identify polypeptides that mimic the function of apoA-1 such as paraoxonase, but have increased half-life and equivalent or more bioactivity than the naturally occurring paraoxonase amino acid sequence. It is also desirable to identify another peptidomimetic of apoA-1 to have association to a natural ligand for apoA-1 as compared to wild-type sequences. Cytokines mediate cellular activities in a number of ways. Cytokines support the proliferation, growth, and differentiation of pluripotential hematopoietic stem cells into vast numbers of progenitors comprising diverse cellular lineages making up a complex immune system. Proper and balanced interactions between the cellular components are necessary for a healthy immune response. The different cellular lineages often respond in a different manner when cytokines are administered in conjunction with other agents Cytokines mediate communication between cells of the immune system, e.g., antigen presenting cells (APCs) and T lymphocytes. Dendritic cells (DCs) are the most potent of antigen presenting cells. See, e.g., Paul (ed.) (1993) Fundamental Immunology 3d ed., Raven Press, NY. Antigen presentation refers to the cellular events in which a proteinaceous antigen is taken up, processed by antigen presenting cells (APC), and then recognized to initiate an immune response. The most active antigen presenting cells have been characterized as the macrophages (which are direct developmental products from monocytes), dendritic cells, and certain B cells. DCs are highly responsive to inflammatory stimuli such as bacterial lipopolysaccharides (LPS), and cytokines such as tumor necrosis factor alpha (TNFalpha). Cytokines or stimuli, such as LPS, can induce a series of phenotypic and functional changes in DC that are collectively referred to as maturation. See, e.g., Banchereau and Schmitt (eds.) (1995) Dendritic Cells in Fundamental and Clinical Immunoloy, Plenum Press, NY. It is desirable to identify polypeptides that mimic the function of cytokine families such as IL-10, IL-2, IL-4, IL-12, and IL-17, but have increased half-life and equivalent or more bioactivity than the naturally occurring IL-10, IL-2, IL-4, IL- , and IL-17 representative amino acid sequences. It is also desirable to identify another peptidomimetic of a cytokine such as IL-17 to have association to a natural receptor for IL-17 as compared to wild-type sequences. Chemists have long sought to extrapolate the power of biological catalysis and recognition to synthetic systems. These efforts have focused largely on low-molecular weight catalysts and receptors. Most biological systems, however, rely almost exclusively on large polymers such as proteins and RNA to perform complex biochemical and/or biological functions. There is a long-felt need to identify synthetic polymers of amino acids which display discrete and predictable folding propensities to mimic natural biological systems. Such polypeptides are designed to provide a molecular equivalent or improved functionality as compared to naturally occurring protein-protein interactions specifically because of their ability to mimic natural interactions in addition to their resistance to natural degradative enzymes in a subject.
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