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Heparin EDTA Patent Application Publication Feb US 20110027771 A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0027771 A1 Deng (43) Pub. Date: Feb. 3, 2011 (54) METHODS AND COMPOSITIONS FORCELL Publication Classification STABILIZATION (51) Int. Cl. (75)75) InventorInventor: tDavid Deng,eng, Mountain rView, V1ew,ar. CA C09KCI2N 5/073IS/00 (2006.01)(2010.01) C7H 2L/04 (2006.01) Correspondence Address: CI2O 1/02 (2006.01) WILSON, SONSINI, GOODRICH & ROSATI GOIN 33/48 (2006.01) 650 PAGE MILL ROAD CI2O I/68 (2006.01) PALO ALTO, CA 94304-1050 (US) CI2M I/24 (2006.01) rsr rr (52) U.S. Cl. ............ 435/2; 435/374; 252/397:536/23.1; (73) Assignee: Arts Health, Inc., San Carlos, 435/29: 436/63; 436/94; 435/6: 435/307.1 (21) Appl. No.: 12/847,876 (57) ABSTRACT Fragile cells have value for use in diagnosing many types of (22) Filed: Jul. 30, 2010 conditions. There is a need for compositions that stabilize fragile cells. The stabilization compositions of the provided Related U.S. Application Data inventionallow for the stabilization, enrichment, and analysis (60) Provisional application No. 61/230,638, filed on Jul. of fragile cells, including fetal cells, circulating tumor cells, 31, 2009. and stem cells. 14 w Heparin EDTA Patent Application Publication Feb. 3, 2011 Sheet 1 of 17 US 2011/0027771 A1 FIG. 1 Heparin EDTA Patent Application Publication Feb. 3, 2011 Sheet 2 of 17 US 2011/0027771 A1 FIG. 2 Cell Equivalent/10 ml blood P=0.282 (n=11) 1 hour 6 hours No Composition C Composition C Patent Application Publication Feb. 3, 2011 Sheet 3 of 17 US 2011/0027771 A1 FIG. 3 35 & 30 25 & S 15 S. S S 10 SS & S S. S. ŠŠŠŠ ŠS SS S Š S SS & Š & SS 24 48 72 96 Hours. After Blood Collection Patent Application Publication Feb. 3, 2011 Sheet 4 of 17 US 2011/0027771 A1 FIG. 4 P<0.05 (n=9) Patent Application Publication Feb. 3, 2011 Sheet 5 of 17 US 2011/0027771 A1 FIG. 5 Fetal Cell CSM Chip Blood Cell BOOd Number Run Morphology Collection ACD ------ ------ ------ Li-Heparin + ------ ------ ++/+++ --- Comp. A ACD+ ---- ------ ------ ------ Comp. D Rare Cell - -- +/++ ------ BCT Patent Application Publication Feb. 3, 2011 Sheet 6 of 17 US 2011/0027771 A1 FIG. 6 Sample ID Method Act Fetal Cells in ProductsACD+Como D 1 s 2 DGC 2 3 DGC 2 S 4 DGC 1 5 DGC 2 2 6 DGC 3 2 7 DGC 0 8 3. 9 CSM 5 2 10 CSM 6 11 CSM 3 2 Patent Application Publication Feb. 3, 2011 Sheet 7 of 17 US 2011/0027771 A1 FIG. 7 ACD + Composition D at 76 hrs Patent Application Publication Feb. 3, 2011 Sheet 8 of 17 US 2011/0027771 A1 maxWWWWWwww.www. rees CSM Procedure x Control ---NNNN NNNN x^\&\&\\\\-8 &x &S 10 mL. Blood 10 mL. Blood CSM Product CSM Waste Chip clogged Or red product color (RBC carryover) were 2x Washal 2x were 2x were 2x DNA train DNA train DNA insion DNA into digital PCR digital PCR digital PCR digital PCR Patent Application Publication Feb. 3, 2011 Sheet 9 of 17 US 2011/0027771 A1 Average F. Direction FIG. 9A Patent Application Publication Feb. 3, 2011 Sheet 10 of 17 US 2011/0027771 A1 Average Flow Direction FIG. 9B Patent Application Publication Feb. 3, 2011 Sheet 11 of 17 US 2011/0027771 A1 Average FW Direction W / FIG. 9C Patent Application Publication Feb. 3, 2011 Sheet 12 of 17 US 2011/0027771 A1 Patent Application Publication Feb. 3, 2011 Sheet 13 of 17 US 2011/0027771 A1 ???? ||| Ll FIG. OC | || |. Patent Application Publication Feb. 3, 2011 Sheet 14 of 17 : k &S 4.*** S & 8 ææ•???« s es FIG. 11 A Patent Application Publication Feb. 3, 2011 Sheet 15 of 17 US 2011/0027771 A1 poolaerouwTuuozeoi»oaa?enou?e ? FIG. 11 B Patent Application Publication Feb. 3, 2011 Sheet 16 of 17 US 2011/0027771 A1 Wit. Without Composition Q Composition Q FIG. 12 Patent Application Publication Feb. 3, 2011 Sheet 17 of 17 US 2011/0027771 A1 AES53 ARRSS is Sis FIG. 13 US 2011/0027771 A1 Feb. 3, 2011 METHODS AND COMPOSITIONS FORCELL 0008. In another aspect, a stabilization composition is pro STABILIZATION vided including: glycine, NAC, glutamine and D-Mannitol and optionally one or more anticoagulants, cell membrane stabilizers, or energy sources. 0001. This application claims priority or the benefit under 0009. In one embodiment, the composition does not 35 U.S.C. 119 of U.S. provisional application No. 61/230,638 include (i) formaldehyde or (ii) an agent that slows cell filed Jul. 31, 2009, the contents of which are fully incorpo metabolism. rated herein by reference. 0010. In one embodiment, the composition does not include (i) potassium dichromate or (ii) a cell membrane FIELD OF THE INVENTION stabilizing agent. 0011. In one embodiment, the anticoagulant comprises at 0002 The present invention relates to compositions and least one antiplatelet drug. method for the stabilization, enrichment, and analysis of frag 0012. In one embodiment, the at least one antiplatelet drug ile cells, including fetal cells, circulating tumor cells, and is selected from the group consisting of theophylline and stem cells. dipyridamole. 0013. In one embodiment, the anticoagulant comprises BACKGROUND OF THE INVENTION one or more of lithium heparin, Sodium heparin, citrate hep 0003 Fragile cells can be used in tests to diagnose the arin, ammonia heparin, sodium citrate, dipyridamole, theo presence or absence of disease. For example, fragile fetal phylline, adenine, adenosine, Warfarin, acenocoumarol, cells isolated from maternal samples can be used for prenatal phenindione, low molecular weight heparin, idraparinux, diagnostics, and fragile circulating tumor cells can be useful fondaparinux, argatroban, lepirudin, bivalirudin, and dabiga for diagnosing various patient conditions. The means by tran. which fragile cells are handled can play a role in various tests. 0014. In one embodiment, the energy source includes glu Fragile cells are often rare, and enrichment of these cells can cose, lactose, fructose, or galactose. aid analysis of these cells. Furthermore, diagnostic tests per 0015. In one embodiment, the antioxidant includes gly formed using these cells can take place hours or days after a cine, n-acetyl-L-cysteine, glutamine, D-Mannitol, Vitamin C sample containing the cells is retrieved. Thus, means for (ascorbic acid), vitamin E (tocopherols and tocotrienols), maintaining the integrity of a rare cell through one or more green tea, ferulic acid, reduced glutathione, melatonin, res enrichment steps and/or over extended periods of time (hours Veratrol, vitamin A (palmitate), beta carotene, vitamin D-3 or days) can play a role in the ability to analyze the cells and (cholecalciferol), selenium (1-seleno methionine). BHA, or perform diagnostic tests. To facilitate enrichment and analy BHT. sis of fragile cells, there is a need for improved compositions, 0016. In one embodiment, the cell membrane stabilizer methods, and kits for stabilizing fragile cells (e.g., fetal cells, includes one or more of potassium dichromate, cadmium circulating tumor cells, and stem cells) in vitro. Compositions chloride, or lithium chloride aldehydes, urea formaldehyde, that stabilize fragile cells can also be used to stabilize other phenol formaldehyde, DMAE (dimethylaminoethanol), cho cell types. lesterol, cholesterol derivatives, high concentrations of mag nesium, vitamin E, and vitamin E derivatives, calcium, cal SUMMARY OF THE INVENTION cium gluconate, taurine, niacin, hydroxylamine derivatives, bimoclomol. Sucrose, astaxanthin, glucose, amitriptyline, 0004. In one aspect, a stabilization composition is pro isomer A hopane tetral phenylacetate, isomer Bhopane tetral vided capable of maintaining at least 50% of fetal cells in a phenylacetate, citicoline, inositol, Vitamin B, Vitamin B com blood sample intact for at least 6 hr. In another aspect, a plex, cholesterol hemisuccinate, Sorbitol, calcium, coenzyme stabilization composition is provided capable of maintaining Q, ubiquinone, Vitamin K. Vitamin K complex, menaquinone, at least 50% of fetal nucleated redblood cells intact for at least Zonegran, Zinc, ginkgo biloba extract, diphenylhydantoin, 6 hr. In one embodiment, the composition is capable of main perforan, polyvinylpyrrolidone, phosphatidylserine, tegre taining at least 50% of fetal nucleated red blood cells intact tol, PABA, disodium cromglycate, nedocromil sodium, phe for at least 12 hr., at least 24 hr, at least 48 hr, at least 72 hr., or nyloin, Zinc citrate, mexitil, dilantin, sodium hyaluronate, or at least 96 hr. In another embodiment, a composition is pro polaxamer 188. vided comprising one or more isolated fetal cells in a stabili 0017. In one embodiment, the cross-linking agent Zation composition. In another embodiment, the composition includes one or more of formaldehyde, formaldehyde deriva is a solution. tives, formalin, glutaraldehyde, glutaraldehyde derivatives, a 0005. In another aspect, a stabilization composition is pro protein cross-linker, a nucleic acid cross-linker, a protein and vided including four or more anticoagulants and two or more nucleic acid cross-linker, primary amine reactive crosslink antioxidants. In another aspect, the stabilization composition ers, sulfhydryl reactive crosslinkers, sulfydryl addition or further includes one or more of the following: one or more disulfide reduction, carbohydrate reactive crosslinkers, car energy sources; one or more cell membrane stabilizers; and boxyl reactive crosslinkers, photoreactive crosslinkers, one or more cross-linking agents. cleavable crosslinkers, AEDP, APG, BASED, BM(PEO)3, 0006. In another aspect, a stabilization composition is pro BM(PEO)4, BMB, BMDB, BMH, BMOE, BS3, BSOCOES, vided including two or more antioxidants and one or more DFDNB, DMA, DMP. DMS, DPDPB, DSG, DSP, DSS, DST, cross-linking agents. DTBP, DTME, DTSSP, EGS, HBVS, sulfo-BSOCOES, 0007. In one embodiment, the stabilization composition Sulfo-DST, or Sulfo-EGS. further includes one or more of the following: one or more 0018.
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