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US 2012/0028896 A1 BOLLEKENS Et Al US 20120O28896A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0028896 A1 BOLLEKENS et al. (43) Pub. Date: Feb. 2, 2012 (54) USE OF FIBROBLAST GROWTH FACTOR Publication Classification FRAGMENTS (51) Int. Cl. A638/18 (2006.01) (75) Inventors: Jacques BOLLEKENS, Bruxelles A6IP27/02 (2006.01) (BE); Salah-Dine CHIBOUT, A6IPI3/2 (2006.01) Tagolsheim (FR); Jacky A6IP II/I6 (2006.01) VONDERSCHER, Cambridge, A6IP 7/16 (2006.01) A6IP 5/00 (2006.01) MA (US); Francois LEGAY, Saint A6IP3/10 (2006.01) Louis (FR): Andre CORDIER, A6IP35/00 (2006.01) Basel (CH); Ruben PAPOIAN, A6IP 9/10 (2006.01) Cincinatti, OH (US); Andreas (52) U.S. Cl. ......................................................... S14/91 SCHERER, Freiburg (DE) (57) ABSTRACT (73) Assignee: NOVARTIS AG A discovery process beginning with an in vivo Screening of proteins, peptides, natural products, classical medicinal com pound or other Substances. The administration of compounds (21) Appl. No.: 13/152,750 to the animal can be either direct or indirect, such as by the administration and expression of cDNA-containing plasmids. (22) Filed: Jun. 3, 2011 Since the discovery process of the invention is based on a non-preconceived hypothesis and whole organism multi-or gan analysis, a compound can be selected for testing in the Related U.S. Application Data absence of any biological selection criteria. The resulting - - - organism-wide pattern of the gene expression changes in the (62) Division of application No. 10,578,470, filed on Apr. GSTON Nics al E. p. the E. at the 18, 2008, now abandoned, filed as application No. molecular and organism-wide levels. The discovery process PCT/EP2004/012572 on Nov. 5, 2004. of the invention then integrates in vivo profiling and internal and external genomic databases to elucidate the function of unknown proteins. The invention further relates to medical (60) Provisional application No. 60/572.247, filed on May uses of fibroblast growth factor 23 (FGF-23), FGF-23 frag 18, 2004, provisional application No. 60/518,073, ments, FGF-23 C-terminal polypeptides, FGF-23 homologs filed on Nov. 7, 2003. and/or FGF-23 variants. Patent Application Publication Feb. 2, 2012 Sheet 1 of 2 US 2012/0028896 A1 Figure 1 LTBP2: latent transforming growth factor beta binding protein 2 human vs mouse (SEQID NO. 5) GPA018 1 qrdpvgryepaggdan rilr rpggsy paaaaak vyslfreqdapvs glap v 50 | : | | | | | | | | | | | | : | | | | | | | | | | | | | | | | | | | | (SEC) ID No. 6) mLTBP2 56 qrdsigryopas radan r1 whpvgshpaaaaak vyslf repaapvpglisps 105 51 craqpgwggpr ripteae arrpsraqqerr 79 . 1D6 ewnqpacIgnpgwlaeae arrpprt qalrr 134 hypothetical protein XP 0974.06 No match in mouse (SEQ ID NO. 7) GPAO19 1 atlggpedestienyaerp. u afkadeflnwhal fes 36 | | | | | | | | | | | | | | | | | | III (SECID No. 8) XP 097405 23 at lg.gpeee stianyas rpeafntpflnidklrs afkade flrwhalf as 72 37 i krklpflnwdafpakkg).rgatpdaq 63 73 ikrklpflnwdafpklk glrsatpdaq 99 (SEQID NO. 9) GPAO2D 1 stiggpee estieryasr peafntpflniakli. afkadefinmhalfe g9 III (SEQ ID No. 8) XP 0974O6 23 atliggpeee stieryasr peafntpflnidklrsafka defin whalfe's 72 5D ikirklipflnwdafpklkglrgatpdaq 75 || | | | | | 73 ikklpflnwidafpklkglrs atpdaq 99 ANGPTLl: angiopoietin-like 1 tuman WS Youse (SEQID No. 10) GPA022 CAYTFlvPeoRITCPICvnikGQDASTIkon ITRHDLExikovlsROKr. As mANGPTLl $YTELYPEQSISPICYNTKPAGT'RimitrindlenukovlszqkteIII 20 (SEQID No. 12) / \Tanslated mouse 5" sequence (SEQ ID NO. 11) (SEQID No. 13) GPAO23 51 stikaitridlenlkdvis cqkr............... 74 (SEQID NO. 14) mANGPTL1 1 ...f/ mitrm dlenlkdvls rekreidvilol v wolvdgnivne wkllrkes 45 Human precursor// sequence Patent Application Publication Feb. 2, 2012 Sheet 2 of 2 US 2012/0028896 A1 Figure 2 Box Plot Column 1 Column 2 US 2012/0028896 A1 Feb. 2, 2012 USE OF FIBROBLAST GROWTH FACTOR 0009 Since the discovery process of the invention is based FRAGMENTS on a non-preconceived hypothesis and whole organism multi organ analysis, polypeptides can be selected for testing in the FIELD OF THE INVENTION absence of any biological selection criteria other than peptide 0001. The invention relates generally to the in vivo testing sequence. The resulting organism-wide pattern of the gene of the efficacy of a compound or composition, and particu expression changes in the transcriptome provides an over larly to the testing and biologically functionalizing of classi view of the activities at the molecular and organism-wide cal Small molecules, natural products, genes, peptides and levels. Accordingly, the unbiased approach of the invention proteins by activity in vivo. regarding the administration of a compound can provide 0002. The invention further relates to medical uses of information about the physiological relationships throughout fibroblast growth factor 23 (FGF-23), FGF-23 fragments, the entire body that are caused by the compound's adminis FGF-23 C-terminal polypeptides, FGF-23 homologs and/or tration. FGF-23 variants, in particular for the manufacture of a medi 0010. The discovery process of the invention then inte cament for the treatment of diseases associated with deregu grates in vivo profiling with internal and external genomic lated angiogenesis or cell proliferative disorders. databases to elucidate the function of unknown proteins, typi cally within few months. The unbiased approach of the inven BACKGROUND OF THE INVENTION tion in regards to the administration of a compound advanta geously provides genomic signatures from multiple organs. 0003 Pharmaceutical companies are interested in evalu The resulting data can be analyzed either by using tools that ating and understanding the function and regulation of newly are known to those of skill in the art or by using tools that discovered genes and gene products (proteins), especially compare the compound signatures produced by the adminis newly discovered genes and proteins, which could help in the tration of the compound among the different organs. This understanding of the mechanisms linked to diseases or com multi-organ analysis is in contrast to standard approaches, pounds action. In addition, the genes and gene products can which, since they do not use an unbiased approach of com become potential drugs or biomarkers. Grenet O, Pharmaco pound administration, do not result in a multi-organ identifi genomics J. 1 (1):11-2 (2001). cation of the function of the compound. Instead the standard 0004. However, a gene sequence alone does not provide approaches provide analysis on a case-by-case basis, which information about the actual function of the protein in the cell can make cross-experimental comparisons difficult. In con or organism physiology. In addition, while the genome has a trast to the standard approaches, the identification of the relatively well defined number of genes, there is no known function of the compound using the method of the invention limit to the possible number of protein variants. The potential allows for the identification of the function of the compound number of proteins encoded by these genes is estimated to be in many metabolic and regulatory pathways. In addition, the from two to at least one-hundred times higher than the num identification of the function of the compound using the ber of genes, since it has recently been found that proteins can method of the invention advantageously results in an under also be produced by splicing at the protein level not just at the standing of the stability of the active compound in the body, a RNA level. property of the administered compound which would other 0005. The current process of drug discovery proceeds wise not be predictable a priori using standard approaches. from single target to single drug product. The current process 0011. The identification of the function of the compound is a long process, frequently with late attrition for lack of using the method of the invention can be multi-step, as one efficacy, wrong design or false indication. step or part of the identification leads to another step or part of 0006 Thus, there is a need in the art for a more efficient the identification, to provide a more complete understanding method for discovering and identifying drug candidates, gene of the administered compound's activity in vivo. For targets and biomarkers. example, the identification of compound function in one organ (such as the spleen) can lead to an understanding of the SUMMARY OF THE INVENTION compound function in other organs. By contrast, the standard 0007. The invention provides a discovery process for bio approaches, which rely on immediate access to tests on a logically functionalizing peptides, proteins, genes, Small limited number of organs, depend on anecdotal evidence molecules and natural products using organism-wide gene from other experiments to further steps in the identification of expression profiling. The discovery process of the invention compound function. proceeds from single lead or drug to multiple targets and 0012. The invention is suitable for several stages of drug indications (as indicated by an impact on any target in the discovery, identifying both drug targets and biomarkers. The cascade chain of a pathway), and multiple drug products, thus discovery process of the invention advantageously delivers an providing rapid guidance to a correct human proof-of-con increased number of validated drug candidates and identified cept. drug targets and biomarkers along with a savings in time, 0008. The discovery process of the invention begins with resources and animals. The discovery process of
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