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WO 2017/019918 Al 2 February 2017 (02.02.2017) P O P C T

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WO 2017/019918 Al 2 February 2017 (02.02.2017) P O P C T (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 2017/019918 Al 2 February 2017 (02.02.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07H 19/173 (2006.01) C07H 19/19 (2006.01) kind of national protection available): AE, AG, AL, AM, C07H 21/00 (2006.01) C07H 19/09 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2016/044595 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 28 July 2016 (28.07.2016) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/198,05 1 28 July 2015 (28.07.2015) US kind of regional protection available): ARIPO (BW, GH, 62/198,1 10 28 July 2015 (28.07.2015) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/220,652 18 September 2015 (18.09.2015) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 62/239,226 8 October 201 5 (08. 10.2015) US TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 62/269,671 18 December 201 5 (18. 12.2015) US DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 62/305,536 9 March 2016 (09.03.2016) US LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (71) Applicant: CARIS SCIENCE, INC. [US/US]; 6655 N . GW, KM, ML, MR, NE, SN, TD, TG). Macarthur Blvd., Irving, TX 75039 (US). Published: (72) Inventors: O'NEILL, Heather; 1252 W Laguna Azul — with international search report (Art. 21(3)) Ave, Mesa, AZ 85202 (US). MAYER, Gunter; Mar- tin-legros Strasse 59, 53123 Bonn (DE). MIGLARESE, — before the expiration of the time limit for amending the Mark; 1620 East Silverwood Drive, Phoenix, AZ 85048 claims and to be republished in the event of receipt of (US). SPETZLER, David; 6045 N . 40th St., Paradise Val amendments (Rule 48.2(h)) ley, AZ 85253 (US). — with sequence listing part of description (Rule 5.2(a)) (74) Agent: AKHAVAN, Ramin; Caris Science, Inc., 6655 N . Macarthur Blvd., Irving, TX 75039 (US). < 00 © o- (54) Title: TARGETED OLIGONUCLEOTIDES (57) Abstract: Methods and compositions are provided for oligonucleotides that bind targets of interest. The targets include cells and microvesicles, such as those derived from various diseases. The oligonucleotides can be used for diagnostic and therapeutic pur- poses. The target of the oligonucleotides can be a target such as PARPl, HISTIHIB, HISTIHID, NCL, FBL, SFPQ, RPL12, ACTB, HIST 1H4A, SSBP 1, NONO, H2AFJ, and DDX2 1, or a complex, submit or fragment thereof. TARGETED OLIGONUCLEOTIDES CROSS REFERENCE This application claims the benefit of U.S. Provisional Patent Application Nos. 62/198,051, filed July 28, 2015; 62/198,110, filed July 28, 2015; 62/220,652, filed September 18, 2015; 62/239,226, filed October 8, 2015; 62/269,671, filed December 18, 2015; and 62/305,536, filed March 9, 2016; all of which applications are incorporated herein by reference in their entirety. This application is related to International Patent Application Nos. PCT/US20 16/02 1632, filed March 9, 2016; and PCT/US2016/040157, filed June 29, 2016; both of which applications are incorporated herein by reference in their entirety. SEQUENCE LISTING SUBMITTED VIA EFS-WEB [0001] The entire content of t e 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: [0002] File Name : 826601_SeqListing_ST25.txt [0003] Date of Creation : July 28. 2016 [0004] Size (bytes) : 897,071 bytes BACKGROUND OF THE INVENTION [0005] 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, including without limitation a breast cancer. [0006] Aptamers are oligomeric nucleic acid molecules having specific binding affinity to molecules, which may be through interactions other than classic Watson-Crick base pairing. Unless otherwise specified, an "aptamer" as the term is used herein can refer to nucleic acid molecules that can be used to characterize a phenotype, regardless of manner of target recognition. Unless other specified, the terms "aptamer," "oligonucleotide," "polynucleotide," or the like may be used interchangeably herein. [0007] 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. [0008] 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: [0009] 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 t e 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. [0010] 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. [0011] 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. [0012] Scalability and cost. Aptamers are chemically synthesized and are readily scaled as needed to meet production demand for diagnostic or therapeutic applications. Whereas difficulties in scaling production are currently limiting the availability of some biologies and the capital cost of a large-scale protein production plant is enormous, a single large-scale oligonucleotide synthesizer can produce upwards of 100 kg/year and requires a relatively modest initial investment. The current cost of goods for aptamer synthesis at the kilogram scale is estimated at $100/g, comparable to that for highly optimized antibodies. [0013] Stability. Aptamers are chemically robust. They are intrinsically adapted to regain activity following exposure to factors such as heat and denaturants and can be stored for extended periods (>1 yr) at room temperature as lyophilized powders. INCORPORATION BY REFERENCE [0014] All publications, patents and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. SUMMARY OF THE INVENTION [0015] Compositions and methods of the invention provide aptamers that bind biomarkers of interest. In various embodiments, oligonucleotide probes of the invention are used in diagnostic, prognostic or theranostic processes to screen a biological sample for the presence or levels of biomarkers, including without limitation surface antigens, determined to provide a relevant readout.
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