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(12) Patent Application Publication (10) Pub. No.: US 2013/0096050 A1 Shandler (43) Pub US 2013 0096.050A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0096050 A1 Shandler (43) Pub. Date: Apr. 18, 2013 (54) HIGHILY ACTIVE POLYPEPTDES AND Publication Classification METHODS OF MAKING AND USING THE SAME (51) Int. Cl. A638/22 (2006.01) (75) Inventor: Scott J Shandler, Philadelphia, PA (US) (52) U.S. Cl. CPC .................................. A61 K38/2278 (2013.01) (73) Assignee: Longevity Biotech, Inc., Philadelphia, USPC .......... 514/1.7:435/7.21: 435/6.13: 530/309; PA (US) 436/501: 514/13.1; 530/303: 514/6.9; 514/7.3; 51475.3 (21) Appl. No.: 13/642,757 (22) PCT Fled: Apr. 22, 2011 (57) ABSTRACT (86) PCT NO.: PCT/US11A33684 This invention relates to novel compositions comprising ana logs of naturally occurring polypeptides, wherein the analog S371 (c)(1), comprises an a-amino acid and at least one B-amino acid. (2), (4) Date: Jan. 2, 2013 Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused Related U.S. Application Data by dysfunctional biochemical or biological pathways. The (60) Provisional application No. 61/327,098, filed on Apr. compositions and methods of this invention are particularly 22, 2010, provisional application No. 61/364,359, useful to identify novel therapeutic modulators of in-vivo filed on Jul. 14, 2010, provisional application No. receptor activity with extended half-lives and relevant bioac 61/405,560, filed on Oct. 21, 2010, provisional appli tivity as compared to the naturally translated polypeptides cation No. 61/445,468, filed on Feb. 22, 2011. upon which the analogs are derived. Patent Application Publication Apr. 18, 2013 Sheet 1 of 4 US 2013/0096.050 A1 Figure 1 io 354 i : 50 OOO 50 53. ki insii wd. ulius A.ii. *d kilww. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 5 5 O O F5 30 3. 350 375 Patent Application Publication Apr. 18, 2013 Sheet 2 of 4 US 2013/0096.050 A1 Figure 2 Mean Residue Ellipticity 15000 cc cric 1 OOC 5OCO t 0 -ocrewAxf OO 21C 22 230 240 2O 2O Patent Application Publication Apr. 18, 2013 Sheet 3 of 4 US 2013/0096.050 A1 Figure 3 PANELA H. R. G5 Ageist Roxie Nisis is is SS 'S it-88 SS-82 -&i is 38 S-8 is 8 Capai's fi PANEL B H. R. G.S. Agorist Riode a's Sist i isi-8s is is 8-38 -8: -8 is 8 - 8 - sist - S.E.E.E.E. E. Patent Application Publication Apr. 18, 2013 Sheet 4 of 4 US 2013/0096.050 A1 Figure 4 PANEL A RR: G5 Artagorist Rio de Norraieed dista 3-88 -88 - I -88 i-3 i-3 - E-8 is sistic i. PANEL B PR Gis Attagonist Mode isities its S. s - S -88 -8° S is - :- - -8 ;-& Copaired a US 2013/0096050 A1 Apr. 18, 2013 HIGHILY ACTIVE POLYPEPTDES AND 0005 HDL cholesterol level is inversely related to the METHODS OF MAKING AND USING THE incidence of coronary heart disease and recently received SAME increasing attention as a novel target in lipid management of treating atherosclerotic vascular disease. Direct vascular pro CROSS-REFERENCE TO RELATED tective effects of HDL have been attributed to apolipoprotein APPLICATIONS (apo) A-I or apoA-I-associated molecules in HDL using direct intravenous injections of homologous HDL.3 recom 0001. This application claims priority to U.S. Provisional binant mutantapoA-Imilano or apoA-I gene therapy, or use of Ser. No. 61/327,098, filed on Apr. 22, 2010; U.S. Provisional transgenic animals overexpressing apoA-I or apoA1-related Ser. No. 61/364,359, filed on Jul. 14, 2010; U.S. Provisional molecules Such as paraoXonase. A recent phase II randomized Ser. No. 61/405,560, filed on Oct. 21, 2010; and U.S. Provi trial showed that 5 weekly intravenous injections of recom sional Ser. No. 61/445,468, filed on Feb. 22, 2011, all of binant apoA-Imilano induced rapid regression of coronary which are herein incorporated by reference in their entirety. atherosclerotic lesions in humans. It is desirable to identify polypeptides that mimic the function of apoA-I Such as FIELD OF THE INVENTION paraoxonase, but have increased half-life and equivalent or more bioactivity than the naturally occurring paraoXonase 0002 The invention relates generally to compositions amino acid sequence. It is also desirable to identify another comprising modified polypeptide sequences with greater peptidomimetic of apoA-I to have association to a natural resistance to degradation and equivalent and/or increased ligand for apoA-I as compared to wild-type sequences. bioactivity as compared to naturally encoded, unmodified polypeptide sequences, and to methods of making the com 0006 Cytokines mediate cellular activities in a number of positions and methods of using the compositions as pharma ways. Cytokines Support the proliferation, growth, and dif ferentiation of pluripotential hematopoietic stem cells into ceutically active agents to treat disease in animals, including vast numbers of progenitors comprising diverse cellular lin humans. eages making up a complex immune system. Proper and balanced interactions between the cellular components are BACKGROUND OF THE INVENTION necessary for a healthy immune response. The different cel 0003. The secretin family is a family of well-conserved lular lineages often respond in a different manner when animal proteins with a variety of biological functions. Bio cytokines are administered in conjunction with other agents. logically active members of the secretin family are generally 0007 Cytokines mediate communication between cells of from about 26 to about 65 amino acids in length and are the immune system, e.g., antigen presenting cells (APCs) and thought to have relatively simple alpha-helical secondary T lymphocytes. Dendritic cells (DCs) are the most potent of structures. Many members are originally produced in vivo as antigen presenting cells. See, e.g., Paul (ed.) (1993) Funda larger pro-peptides, which are eventually converted in the mental Immunology 3d ed., Raven Press, NY. Antigen pre active forms. Members of the secretin family include the sentation refers to the cellular events in which a proteinaceous following proteins: GHRF, GIP, GLP-1, Glucagon, PACAP antigen is taken up, processed by antigen presenting cells 27, PACAP-38, PHM, PrP, and secretin. The q25 region of (APC), and then recognized to initiate an immune response. chromosome 6 on the human genome encodes another secre The most active antigen presenting cells have been character tin family member that is 170 amino acids long which ized as the macrophages (which are direct developmental becomes post-translationally cleaved to form vasoactive products from monocytes), dendritic cells, and certain B intestinal peptide (VIP). The active form of the VIP polypep cells. DCs are highly responsive to inflammatory stimuli Such tide is a 28 amino acid protein that functions, among other as bacterial lipopolysaccharides (LPS), and cytokines such as ways, to reduce arterial blood pressure, to increase vasodila tumor necrosis factor alpha (TNFalpha). Cytokines or tion of blood vessel walls, to relax smooth muscle in the stimuli. Such as LPS, can induce a series of phenotypic and respiratory system and gastrointestinal tissues, reduce functional changes in DC that are collectively referred to as inflammatory responses through both promotion of Th2 dif maturation. See, e.g., Banchereau and Schmitt (eds.) (1995) ferentiation as well as the reduction of Th1 responses, modu Dendritic Cells in Fundamental and Clinical Immunoloy, Ple late both the innate and adaptive immune response, and to num Press, NY. It is desirable to identify polypeptides that stimulate secretion of electrolytes in the gut. VIP has also mimic the function of cytokine families such as IL-10, IL-2, been shown to be active in the central nervous system as a IL-4, IL-12, and IL-17, but have increased half-life and neurotransmitter and in communication with lymphocytes. equivalent or more bioactivity than the naturally occurring Bioactivity of VIP is transmuted through three known recep IL-10, IL-2, IL-4, IL-12, and IL-17 representative amino acid tor subtypes: VIP, R, VIPR, and PACR. These receptors are sequences. It is also desirable to identify another peptidomi known to induce cAMP concentration as well as stimulate the metic of a cytokine Such as IL-17 to have association to a production of intracellular calcium. Their affinities for secre natural receptor for IL-17 as compared to wild-type tins such as VIP vary depending upon the subtype and the Sequences. amino acid sequence of the ligand. 0008 Chemists have long sought to extrapolate the power 0004 Secretin family members have short half-lives. For of biological catalysis and recognition to synthetic systems. instance, VIP has a half-life of about two minutes in the blood These efforts have focused largely on low-molecular weight stream. It is desirable to identify polypeptides that mimic the catalysts and receptors. Most biological systems, however, function of secretins such as VIP, but have increased half-life rely almost exclusively on large polymers such as proteins and equivalent or more bioactivity than the naturally occur and RNA to perform complex biochemical and/or biological ring VIP amino acid sequence. It is also desirable to identify functions. There is a long-felt need to identify synthetic poly another peptidomimetic of VIP to have association to one mers of amino acids which display discrete and predictable receptor Subtype over another secretin receptor. folding propensities to mimic natural biological systems. US 2013/0096050 A1 Apr. 18, 2013 Such polypeptides are designed to provide a molecular B-amino acids in the analog is from about 14 percent to about equivalent or improved functionality as compared to natu 50 percent of the total number of amino acids of the analog.
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