(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 13 September 2007 (13.09.2007) WO 2007/103515 A2 (51) International Patent Classification: CA 95008 (US). CRAMERI, Andreas [CH/US]; 12020 A61K 38/16 (2006.01) C40B 40/10 (2006.01) Green Hills Court, Los Altos Hills, CA 94022 (US). C40B 40/08 (2006.01) C07K 14/47 (2006.01) (74) Agents: WONG, Karen, K. et al.; Wilson Sonsini (21) International Application Number: Goodrich & Rosati, 650 Page Mill Road, Palo Alto, CA PCT/US2007/005952 94306-1050 (US). (22) International Filing Date: 6 March 2007 (06.03.2007) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (25) Filing Language: English AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, (26) Publication Language: English GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, (30) Priority Data: LT,LU, LY,MA, MD, MG, MK, MN, MW, MX, MY, MZ, 60/743,410 6 March 2006 (06.03.2006) US NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, 60/743,622 21 March 2006 (2 1.03.2006) US SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, 11/528,927 27 September 2006 (27.09.2006) US TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW 11/528,950 27 September 2006 (27.09.2006) US (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): AMU- kind of regional protection available): ARIPO (BW, GH, NIX, INC. [US/US]; 500 Ellis Street, Suite B, Mountain GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, View, C 94043 (US). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (72) Inventors; and FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, (75) Inventors/Applicants (for US only): SCHELLEN- PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, BERGER, Volker [DE/US]; 914 Moreno Avenue, Palo GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Alto, California 94303 (US). STEMMER, Willem, P. [NL/US]; 108 Kathy Court, Los Gatos, CA 95030 (US). Published: WANG, Chia-wei [-/US]; 3444 El Camino Real #307, — without international search report and to be republished Santa Clara, CA 95051 (US). SCHOLLE, Michael, D. upon receipt of that report [US/US]; 100 N. Whisman Road, Apt. 3613, Mountain View, CA 94043 (US). POPKOV, Mikhail [CA/US]; 9917 For two-letter codes and other abbreviations, refer to the "G uid Aviary Drive, San Diego, CA 92131 (US). GORDON, ance Notes on Codes and Abbreviations" appearing at the beg in Nathaniel, C. [US/US]; 1415 Sharp Court, Campbell, ning of each regular issue of the PCT Gazette. (54) Title: UNSTRUCTURED RECOMBINANT POLYMERS AND USES THEREOF (57) Abstract: The present invention provides unstructured recombinant polymers (URPs) andproteins containing one or more of the URPs. The present invention also provides microproteins, toxins and other related proteinaceous entities, as well as genetic packages displaying these entities. The present invention also provides recombinant polypeptides including vectors encoding the subject proteinaceous entities, as well as host cells comprising the vectors. The subject compositions have a variety of utilities including a range of pharmaceutical applications. UNSTRUCTURED RECOMBINANT POLYMERS AND USES THEREOF CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No. 60/743,410 filed March 6, 2006, which application is incorporated herein by reference. This application is a continuation-in- ρart application of 11/528,927 and 11/528,950, filed on September 27, 2006, which in turn claim priority to provisional applications serial nos. 60/721,270, 60/721,188, filed on 9/27/2005 and 60/743,622 filed on 03/21/06, all of which are herein incorporated by reference in their entirety. BACKGROUND OF THE INVENTION [0002] It has been well documented that properties of proteins, in particular plasma clearance and imrnunogenicity, can be improved by attaching hydrophilic polymers to these proteins (Kochendoerfer, G. (2003) Expert Opin Biol Ther, 3: 1253-61), (Greenwald, R. B., et al. (2003) Adv Drug Deliv Rev, 55: 217- 50), (Harris, J. M., et al. (2003) Nat Rev Drug Discov, 2: 214-2 1). Examples of polymer-modified proteins that have been approved by the FDA for treatment of patients are Adagen, Oncaspar, PEG-Intron, Pegasys, Somavert, and Neulasta. Many more polymer-modified proteins are in clinical trials. These polymers exert their effect by increasing the hydrodynamic radius (also called Stokes' radius) of the modified protein relative to the unmodified protein, which reduces the rate of clearance by kidney filtration (Yang, K., et al. (2003) Protein Eng, 16: 761-70). In addition, polymer attachment can reduce interaction of the modified protein with other proteins, cells, or surfaces. In particular, polymer attachment can reduce interactions between the modified protein and antibodies and other components of the immune system thus reducing the formation of a host immune response to the modified protein. Of particular interest is protein modification by PEGylation, i.e. by attaching linear or branched polymers of polyethylene glycol. Reduced immunogenicity upon PEGylation was shown for example for phenylalanine ammonia lyase (Garnez, A., et al. (2005) MoI Ther, 11: 986-9), antibodies (Deckert, P. M., et al. (2000) IntJ Cancer, 87: 382-90.), Staphylokinase (Collen, D., et al. (2000) Circulation, 102: 1766-72), and hemoglobin (Jin, C , et al. (2004) Protein Pept Lett, 11: 353-60). Typically, such polymers are conjugated with the protein of interest via a chemical modification step after the unmodified protein has been purified. [0003] Various polymers can be attached to proteins. Of particular interest are hydrophilic polymers that have flexible conformations and are well hydrated in aqueous solutions. A frequently used polymer is polyethylene glycol (PEG). These polymers tend to have large hydrodynamic radi relative to their molecular weight (Kubetzko, S., et al. (2005) MoI Pharmacol, 68: 1439-54). The attached polymers tend to have limited interactions with the protein they have been attached to and thus the polymer-modified protein retains its relevant functions. [0004] The chemical conjugation of polymers to proteins requires complex multi-step processes. Typically, the protein component needs to be produced and purified prior to the chemical conjugation step. The conjugation step can result in the formation of product mixtures that need to be separated leading to significant product loss. Alternatively, such mixtures can be used as the final pharmaceutical product. Some examples are currently marketed PEGylated Interferon-alpha products that are used as mixtures (Wang, B. L., etal. (1998) JSubmicrosc Cytol Pathol, 30: 503-9; Dhalluin,C , et al. (2005) Bioconjug Chem, 16: 504-17). -Such mixtures are difficult to manufacture and characterize and they contain isomers with reduced or no therapeutic activity. [0005] Methods have been described that allow the site-specific addition of polymers like PEG. Examples are the selective PEGylation at a unique glycosylation site of the target protein or the selective PEGylation of a non-natural amino acid that has been engineered into the target proteins. In some cases it has been possible to selectively PEGylate the N-terminus of a protein while avoiding PEGylation of lysine side chains in the target protein by carefully controlling the reaction conditions. Yet another approach for the site-specific PEGylation of target proteins is the introduction of cysteine residues that allow selective conjugation. All these methods have significant limitations. The selective PEGylation of the N-terminus requires careful process control and side reactions are difficult to eliminate. The introduction of cysteines for PEGylation can interfere with protein production and/or purification. The specific introduction of non-natural amino acids requires specific host organisms for protein production. A further limitation of PEGylation is that PEG is typically manufactured as a mixture of polymers with similar but not uniform length. The same limitations are inherent in many other chemical polymers. [0006] Chemical conjugation using multifunctional polymers which would allow the synthesis of products with multiple protein modules is even more complex then the polymer conjugation of a single protein domain. [0007] Recently, it has been observed that some proteins of pathogenic organisms contain repetitive peptide sequences that seem to lead to a relatively long serum halflife of the proteins containing these sequences (Alvarez, P., et al. (2004) J Biol Chem, 279: 3375-81). It has also been demonstrated that oligomeric sequences that are based on such pathogen-derived repetitive sequences can be fused to other proteins resulting in increased serum halflife. However, these pathogen-derived oligomers have a number of deficiencies. The pathogen-derived sequences tend to be immunogenic. It has been described that the sequences can be modified to reduce their immunogenicity. However, no attempts have been reported to remove T cell epitopes from the sequences contributing to the formation of immune reactions. Furthermore, the pathogen-derived sequences have not been optimized for pharmacological applications which require