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WO 2011/014741 Al (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 3 February 2011 (03.02.2011) WO 2011/014741 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 5/00 (2006.0 1) C12N 5/02 (2006.0 1) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US2010/043854 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 30 July 2010 (30.07.2010) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/230,638 31 July 2009 (3 1.07.2009) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ARTEMIS HEALTH, INC. [US/US]; 153 1 Industrial ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Road, San Carlos, CA 94070 (US). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventor; and LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, (75) Inventor/Applicant (for US only): DENG, David SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, [US/US]; 49 Showers Drive Unit T409, Mountain View, GW, ML, MR, NE, SN, TD, TG). CA 94040 (US). Published: (74) Agents: SKUBATCH, Maya et al; Wilson Sonsini Goodrich & Rosati, 650 Page Mill Road, Palo Alto, CA — with international search report (Art. 21(3)) 94304-1050 (US). (54) Title: METHODS AND COMPOSITIONS FOR CELL STABILIZATION (57) Abstract: Fragile cells have value for use in diagnosing many types of conditions. There is a need for compositions that sta- bilize fragile cells. The stabilization compositions of the provided invention allow for the stabilization, enrichment, and analysis of fragile cells, including fetal cells, circulating tumor cells, and stem cells. METHODS AND COMPOSITIONS FOR CELL STABILIZATION [0001] This application claims priority or the benefit under 35 U.S.C. 119 of U.S. provisional application No. 61/230,638 filed July 31, 2009, the contents of which are fully incorporated herein by reference. FIELD OF THE INVENTION [0002] The present invention relates to compositions and method for the stabilization, enrichment, and analysis of fragile cells, including fetal cells, circulating tumor cells, and stem cells. BACKGROUND OF THE INVENTION [0003] Fragile cells can be used in tests to diagnose the presence or absence of disease. For example, fragile fetal cells isolated from maternal samples can be used for prenatal diagnostics, and fragile circulating tumor cells can be useful for diagnosing various patient conditions. The means by which fragile cells are handled can play a role in various tests. Fragile cells are often rare, and enrichment of these cells can aid analysis of these cells. Furthermore, diagnostic tests performed using these cells can take place hours or days after a sample containing the cells is retrieved. Thus, means for maintaining the integrity of a rare cell through one or more enrichment steps and/or over extended periods of time (hours or days) can play a role in the ability to analyze the cells and perform diagnostic tests. To facilitate enrichment and analysis of fragile cells, there is a need for improved compositions, methods, and kits for stabilizing fragile cells (e.g., fetal cells, circulating tumor cells, and stem cells) in vitro. Compositions that stabilize fragile cells can also be used to stabilize other cell types. SUMMARY OF THE INVENTION [0004] In one aspect, a stabilization composition is provided capable of maintaining at least 50% of fetal cells in a blood sample intact for at least 6 hr. In another aspect, a stabilization composition is provided capable of maintaining at least 50% of fetal nucleated red blood cells intact for at least 6 hr. In one embodiment, the composition is capable of maintaining at least 50% of fetal nucleated red blood cells intact for at least 12 hr, at least 24 hr, at least 48 hr, at least 72 hr, or at least 96 hr. In another embodiment, a composition is provided comprising one or more isolated fetal cells in a stabilization composition. In another embodiment, the composition is a solution. [0005] In another aspect, a stabilization composition is provided including four or more anticoagulants and two or more antioxidants. In another aspect, the stabilization composition further includes one or more of the following: one or more energy sources; one or more cell membrane stabilizers; and one or more cross-linking agents. [0006] In another aspect, a stabilization composition is provided including two or more antioxidants and one or more cross-linking agents. [0007] In one embodiment, the stabilization composition further includes one or more of the following: one or more anticoagulants; one or more energy sources; and one or more cell membrane stabilizers. [0008] In another aspect, a stabilization composition is provided including: glycine, NAC, glutamine and D- Mannitol and optionally one or more anticoagulants, cell membrane stabilizers, or energy sources. [0009] In one embodiment, the composition does not include (i) formaldehyde or (ii) an agent that slows cell metabolism. [0010] In one embodiment, the composition does not include (i) potassium dichromate or (ii) a cell membrane stabilizing agent. [0011] In one embodiment, the anticoagulant comprises at least one antiplatelet drug. [0012] In one embodiment, the at least one antiplatelet drug is selected from the group consisting of theophylline and dipyridamole. [0013] In one embodiment, the anticoagulant comprises one or more of lithium heparin, sodium heparin, citrate heparin, ammonia heparin, sodium citrate, dipyridamole, theophylline, adenine, adenosine, Warfarin, acenocoumarol, phenindione, low molecular weight heparin, idraparinux, fondaparinux, argatroban, lepirudin, bivalirudin, and dabigatran. [0014] In one embodiment, the energy source includes glucose, lactose, fructose, or galactose. [0015] In one embodiment, the antioxidant includes glycine, n-acetyl-L-cysteine, glutamine, D-Mannitol, vitamin C (ascorbic acid), vitamin E (tocopherols and tocotrienols), green tea, ferulic acid, reduced glutathione, melatonin, resveratrol, vitamin A (palmitate), beta carotene, vitamin D-3 (cholecalciferol), selenium (1-seleno methionine), BHA, or BHT. [0016] In one embodiment, the cell membrane stabilizer includes one or more of potassium dichromate, cadmium chloride, or lithium chloride aldehydes, urea formaldehyde, phenol formaldehyde, DMAE (dimethylaminoethanol), cholesterol, cholesterol derivatives, high concentrations of magnesium, vitamin E, and vitamin E derivatives, calcium, calcium gluconate, taurine, niacin, hydroxylamine derivatives, bimoclomol, sucrose, astaxanthin, glucose, amitriptyline, isomer A hopane tetral phenylacetate, isomer B hopane tetral phenylacetate, citicoline, inositol, vitamin B, vitamin B complex, cholesterol hemisuccinate, sorbitol, calcium, coenzyme Q, ubiquinone, vitamin K, vitamin K complex, menaquinone, zonegran, zinc, ginkgo biloba extract, diphenylhydantoin, perftoran, polyvinylpyrrolidone, phosphatidylserine, tegretol, PABA, disodium cromglycate, nedocromil sodium, phenyloin, zinc citrate, mexitil, dilantin, sodium hyaluronate, orpolaxamer 188. [0017] In one embodiment, the cross-linking agent includes one or more of formaldehyde, formaldehyde derivatives, formalin, glutaraldehyde, glutaraldehyde derivatives, a protein cross-linker, a nucleic acid cross- linker, a protein and nucleic acid cross-linker, primary amine reactive crosslinkers, sulfhydryl reactive crosslinkers, sulfydryl addition or disulfide reduction, carbohydrate reactive crosslinkers, carboxyl reactive crosslinkers, photoreactive crosslinkers, cleavable crosslinkers, AEDP, APG, BASED, BM(PEO)3, BM(PEO)4, BMB, BMDB, BMH, BMOE, BS3, BSOCOES, DFDNB, DMA, DMP, DMS, DPDPB, DSG, DSP, DSS, DST, DTBP, DTME, DTSSP, EGS, HBVS, sulfo-BSOCOES, Sulfo-DST, or Sulfo-EGS. [0018] In one embodiment, the composition further includes one or more of PEG-200, PEG-300, PEG-400, PEG-600, PEG-1000, PEG-1450, PEG-3350, PEG-4000, PEG-6000, PEG-8000, PEG-20,000, imidazolidinyl urea, diazolidinyl urea, calcium propionate, sodium nitrate, sodium nitrite, sulfites, sulfur dioxide, sodium bisulfite, potassium hydrogen sulfite, disodium EDTA, ethanol, or methylchloroisothiazolinone. [0019] In one embodiment, the composition further comprises a buffer. [0020] In one embodiment, the buffer comprises one or more of phosphate buffered saline (PBS), TAPS, Bicine, Tris, Tricine, HEPES, TES, MOPS, PIPES, Cacodylate, or MES. [0021] In another aspect, a method for stabilizing a cell or cellular component is provided comprising contacting said cell or cellular component with a composition of any one of claims 6-10. [0022] In another embodiment, the cellular component is cell-free DNA. In another embodiment, the cell is a fetal cell in a maternal blood sample. [0023] In another aspect, a
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