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WO 2014/068408 A2 8 May 2014 (08.05.2014) P O P C T

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(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 2014/068408 A2 8 May 2014 (08.05.2014) P O P C T (51) International Patent Classification: Not classified 1249 East Spence Ave, Apt. 218, Tempe, AZ 85281 (US). SPETZLER, David; 13539 N. 95th Way, Scottsdale, AZ (21) International Application Number: 85260 (US). HORNUNG, Tassilo; 1249 East Spence Ave, PCT/IB20 13/003092 Apt. 218, Tempe, AZ 85281 (US). SCHAFER, Frank; (22) International Filing Date: Eichenwand 26, 40627 Dusseldorf (DE). XIAO, Nick; 23 October 2013 (23.10.201 3) 1371 1 Valley Oak Cir., Rockville, MD 20850 (US). (25) Filing Language: English (74) Agent: ROQUES, Sarah, Elizabeth; J.A. Kemp, 14 South Square, Gray's Inn, London WC1R 5JJ (GB). Publication Language: English (81) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of national protection available): AE, AG, AL, AM, 61/717,566 23 October 2012 (23. 10.2012) US AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 61/73 1,419 29 November 2012 (29. 11.2012) US BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 61/735,915 11 December 2012 ( 11. 12.2012) u s DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 61/748,437 2 January 20 13 (02.01 .2013) u s HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 61/749,773 7 January 2013 (07.01 .2013) u s KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 61/750,33 1 8 January 20 13 (08.01 .2013) u s MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 61/754,471 18 January 2013 (18.01.2013) u s OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 61/767,13 1 20 February 2013 (20.02.2013) u s SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 61/769,064 25 February 2013 (25.02.2013) u s TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 61/805,365 26 March 2013 (26.03.2013) u s ZW. 61/808,144 3 April 2013 (03.04.2013) u s 61/820,419 7 May 2013 (07.05.2013) u s (84) Designated States (unless otherwise indicated, for every 61/826,957 23 May 20 13 (23.05.2013) u s kind of regional protection available): ARIPO (BW, GH, 61/838,762 24 June 2013 (24.06.2013) u s GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 61/843,256 5 July 2013 (05.07.2013) u s UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 61/862,809 6 August 2013 (06.08.2013) u s TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 61/863,828 8 August 2013 (08.08.2013) u s EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 61/866,014 14 August 2013 (14.08.2013) u s MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 61/867,978 20 August 2013 (20.08.2013) u s TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, 61/871,107 28 August 2013 (28.08.2013) u s KM, ML, MR, NE, SN, TD, TG). 61/874,621 6 September 2013 (06.09.2013) u s Published: (71) Applicant: CARIS LIFE SCIENCES SWITZERLAND — without international search report and to be republished HOLDINGS, S.A.R.L. [CH/CH]; St. Jacobstrasse 199, upon receipt of that report (Rule 48.2(g)) Citygate, CH-4052 Basel (CH). — with sequence listing part of description (Rule 5.2(a)) (72) Inventors: HALBERT, David; 3 103 Carisbrooke C , Colleyville, TX 76034 (US). DOMENYUK, Valeriy; < oo 00 o (54) Title: APTAMERS AND USES THEREOF (57) Abstract: Methods and compositions are provided for specific aptamers and aptamer pools that bind biomarkers of interest o such as microvesicle surface antigens or functional fragments of microvesicle surface antigens. In various embodiments, aptamers of the invention are used in diagnostic, prognostic, or theranostic processes to screen a biological sample for the presence or levels of biomarkers such as micro vesicles that are determined to provide a diagnostic, prognostic, or theranostic readout. The diagnosis, pro - gnosis, or theranosis may be related to cancer or other diseases and disorders. The invention also provides methods and composition to facilitate aptamer library screening and aptamer detection methods. APTAMERS AND USES THEREOF CROSS REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Application Nos. 61/717,566, filed October 23, 2012; 61/73 1,419, filed November 29, 2012; 61/735,915, filed December 11, 2012; 61/748,437, filed January 2, 2013; 61/749,773, filed January 7, 2013; 61/750,33 1, filed January 8, 2013; 61/754,471, filed January 18, 2013; 61/767,13 1, filed February 20, 2013; 61/769,064, filed February 25, 2013; 61/805,365, filed March 26, 2013; 61/808,144, filed April 3, 2013; 61/820,419, filed May 7, 2013; 61/826,957, filed May 23, 2013; 61/838,762, filed June 24, 2013; 61/843,256, filed July 5, 2013; 61/862,809, filed August 6, 2013; 61/863,828, filed August 8, 2013; 61/866,014, filed August 14, 2013; 61/867,978, filed August 20, 2013; 61/871,107, filed August 28, 2013; and 61/874,621, filed September 6, 2013; all of which applications are incorporated herein by reference in their entirety. SEQUENCE LISTING SUBMITTED VIA EFS-WEB [0002] The entire content of the following electronic submission of the sequence listing via the USPTO EFS- WEB server, as authorized and set forth in MPEP §1730 II.B.2(a), is incorporated herein by reference in its entirety for all purposes. The sequence listing is within the electronically filed text file that is identified as follows: [0003] File Name : 3790181 1601SeqList.txt [0004] Date of Creation: October 23, 2013 [0005] Size (b tes : 82,464,193 bytes BACKGROUND OF THE INVENTION [0006] The invention relates generally to the field of aptamers capable of binding to microvesicle surface antigens, which are useful as therapeutics in and diagnostics of cancer and/or other diseases or disorders in which microvesicles implicated. The invention further relates to materials and methods for the administration of aptamers capable of binding to microvesicles. The microvesicles may be derived from cells indicative of cancer. [0007] Aptamers are nucleic acid molecules having specific binding affinity to molecules through interactions other than classic Watson-Crick base pairing. [0008] Aptamers, like peptides generated by phage display or monoclonal antibodies ("mAbs"), are capable of specifically binding to selected targets and modulating the target's activity, e.g., through binding aptamers may block their target's ability to function. Created by an in vitro selection process from pools of random sequence oligonucleotides, aptamers have been generated for over 100 proteins including growth factors, transcription factors, enzymes, immunoglobulins, and receptors. A typical aptamer is 10-15 kDa in size (30-45 nucleotides), binds its target with sub-nanomolar affinity, and discriminates against closely related targets (e.g., aptamers will typically not bind other proteins from the same gene family). A series of structural studies have shown that aptamers are capable of using the same types of binding interactions (e.g., hydrogen bonding, electrostatic complementarity, hydrophobic contacts, steric exclusion) that drive affinity and specificity in antibody-antigen complexes. [0009] Aptamers have a number of desirable characteristics for use as therapeutics and diagnostics including high specificity and affinity, biological efficacy, and excellent pharmacokinetic properties. In addition, they offer specific competitive advantages over antibodies and other protein biologies, for example: [0010] Speed and control. Aptamers are produced by an entirely in vitro process, allowing for the rapid generation of initial leads, including therapeutic leads. In vitro selection allows the specificity and affinity of the aptamer to be tightly controlled and allows the generation of leads, including leads against both toxic and non- immunogenic targets. [0011] Toxicity and Immunogenicity. Aptamers as a class have demonstrated little or no toxicity or immunogenicity. In chronic dosing of rats or woodchucks with high levels of aptamer (10 mg/kg daily for 90 days), no toxicity is observed by any clinical, cellular, or biochemical measure. Whereas the efficacy of many monoclonal antibodies can be severely limited by immune response to antibodies themselves, it is extremely difficult to elicit antibodies to aptamers most likely because aptamers cannot be presented by T-cells via the MHC and the immune response is generally trained not to recognize nucleic acid fragments. [0012] Administration. Whereas most currently approved antibody therapeutics are administered by intravenous infusion (typically over 2-4 hours), aptamers can be administered by subcutaneous injection (aptamer bioavailability via subcutaneous administration is >80% in monkey studies (Tucker et al., J. Chromatography B. 732: 203-212, 1999)). This difference is primarily due to the comparatively low solubility and thus large volumes necessary for most therapeutic mAbs. With good solubility (>150 mg/mL) and comparatively low molecular weight (aptamer: 10-50 kDa; antibody: 150 kDa), a weekly dose of aptamer may be delivered by injection in a volume of less than 0.5 mL. In addition, the small size of aptamers allows them to penetrate into areas of conformational constrictions that do not allow for antibodies or antibody fragments to penetrate, presenting yet another advantage of aptamer-based therapeutics or prophylaxis.
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  • Table of Contents Table of Contents

    Table of Contents Table of Contents

    Table of contents Table of contents................................................................................................................. 1 Summary ............................................................................................................................. 3 Abbreviations ...................................................................................................................... 4 Gene Symbols I - Incidentals .............................................................................................. 5 Gene symbols II - Target Gene Names ............................................................................... 6 1. Introduction........................................................................................................... 12 1.1. The Pathos of the Crab ..................................................................................... 12 1.2. Cancer in the Molecular Age - a genetic and epigenetic disease..................... 13 1.3. Tumoral evolution............................................................................................. 14 1.4. DNA repair systems .......................................................................................... 17 1.4.1. DNA Mismatch Repair.............................................................................. 18 1.4.2. Double-strand Break Repair..................................................................... 19 1.4.3. Direct Repair...........................................................................................