Source: https://patents.google.com/patent/US9046539B2/en
Timestamp: 2019-08-21 03:51:31
Document Index: 208663844

Matched Legal Cases: ['application No. 08770383', 'Application No. 13169486', 'Application No. 08770383', 'Application No. 2010', 'Application No. 2010', 'Application No. 200880101850', 'Application No. 200880101850', 'Application No. 2010', 'application No. 13169486', 'application No. 13169517', 'Application No. 2008261868']

US9046539B2 - Lipoprotein analysis by differential charged-particle mobility - Google Patents
Lipoprotein analysis by differential charged-particle mobility Download PDF
US9046539B2
US9046539B2 US14/226,089 US201414226089A US9046539B2 US 9046539 B2 US9046539 B2 US 9046539B2 US 201414226089 A US201414226089 A US 201414226089A US 9046539 B2 US9046539 B2 US 9046539B2
US14/226,089
US20140287530A1 (en
Gloria Kwangja Lee
2007-06-08 Priority to US11/760,672 priority Critical patent/US8247235B2/en
2012-08-20 Priority to US13/589,404 priority patent/US8709818B2/en
2014-03-26 Application filed by Quest Diagnostics Investments LLC filed Critical Quest Diagnostics Investments LLC
2014-03-26 Priority to US14/226,089 priority patent/US9046539B2/en
2014-09-25 Publication of US20140287530A1 publication Critical patent/US20140287530A1/en
2015-06-02 Publication of US9046539B2 publication Critical patent/US9046539B2/en
This application is a Continuation of U.S. application Ser. No. 13/589,404, filed Aug. 20, 2012, now U.S. Pat. No. 8,709,818, which is a Divisional of U.S. application Ser. No. 11/760,672, filed Jun. 8, 2007, now U.S. Pat. No. 8,247,235, the entire contents of each are incorporated herein by reference for all purposes in their entireties.
FIG. 1 shows the effect of density on lipoprotein recovery from a plasma sample during a 3.7 hr ultracentrifugation. Samples were prepared in duplicate using different density solutions and centrifugation for 3.7 hr. After collecting the lipoprotein fraction, it was dialyzed before analysis by Ion Mobility. Each panel shows the profile of each replicate. Solution densities: A=1.23 g/mL; B=1.181 g/mL; C=1.170 g/mL; D=1.165 g/mL The abscissa is lipoprotein diameter (nm), and the ordinate is an arbitrarily scaled mass coordinate, which mass coordinate is linearly related to the actual number of particles counted as a function of size (i.e., diameter).
Table 1 describes the standard classes and subclass designations assigned to various lipoprotein fractions using traditional gel electrophoresis measurements: very low density lipoproteins (VLDLs) with subclasses VLDL I and II; intermediate density lipoproteins (IDLs) with subclasses IDL I and II; low density lipoproteins (LDLs) with subclasses I, IIa, IIb, IIIa, IIIb, IVa and IVb; and high density lipoproteins (HDLs), which typically includes several subclasses, such as HDL IIa, IIb, IIIa, IIIb, and IIIc.
Class Acronym Name
Subclass Density (g/mL) Particle Diameter (Å)
Z = neC c 3 ⁢ π ⁢ ⁢ η ⁢ ⁢ d ( 2 )
where n=number of charges on the particle (in this case a single charge), e=1.6.×.10−19 coulombs/charge, Cc=particle size dependent slip correction factor, .η=gas viscosity, and d=particle diameter. Accordingly, solving for d, provides the following relationship:
d = neC c 3 ⁢ π ⁢ ⁢ η ⁢ E V . ( 3 )
Historically, in preparation for centrifugation, a plasma specimen could be density-adjusted to a specific density using high purity solutions or solids of inorganic salts, e.g., sodium chloride (NaCl), sodium bromide (NaBr) and the like. In some previous protocols, the specific density would be chosen to be greater than or equal to the highest density of the lipoprotein material to be analyzed, so that the lipoprotein material would float when density stratified. “Density stratified” and like terms refer to the layering of components in a solution subjected to centrifugation. These densities are tabulated in Table 1, table of lipoprotein classes, subclasses, densities, and sizes. The density-adjusted sample could then be ultracentrifuged for example for approximately 18 hours at 100,000×G to separate the non-lipoprotein proteins from the lipoproteins. Non-lipoprotein proteins, particularly albumin, are removed from the plasma specimen, preferably by this ultracentrifugation step. The lipoproteins float to the top of the sample during ultracentrifugation. Accordingly, by sequentially centrifuging from lowest density to highest density of the density adjustment, the various classes and subclasses of lipoproteins could be sequentially extracted. Typically, a dialysis step would be required following extraction of a centrifuged sample to remove salts introduced for adjustment of density, which dialysis step would typically require 4-12 hrs under conditions well known in the art.
With reference to FIG. 3, under the conditions employed for FIG. 3 (experimental conditions of Example 2) approximately equal recovery of Apo A1 and Apo B after centrifugation are observed, indicating that lower density obtained with D2O does not result in selective recovery of larger less dense particles.
In some embodiments of aspects provided herein which contemplate centrifugation of sample containing lipoproteins and non-lipoprotein components, the sample further comprises an albumin-binding compound under conditions suitable to allow formation of a complex comprising albumin and albumin-binding compound. Representative albumin-binding compounds include, without limitation, aromatic albumin-binding dyes. The aromatic albumin-binding dye may comprise a diazo dye; an alkali metal salt, alkaline earth metal salt, or amine salt of said diazo dye; a sulfonic acid dye; a physiologically-acceptable alkali metal salt, alkaline earth metal salt, or amine salt of said sulfonic acid dye; or mixtures thereof. Aromatic albumin-binding dyes particularly useful in the present invention include Reactive Blue 2, Evans Blue, Trypan Blue, Bromcresol Green, Bromcresol Purple, Methyl Orange, Procion red HE 3B, and the like. In certain embodiments, the albumin-binding compound is an analog of nicotinamide adenine dinucleotide (NAD). Representative NAD analogs suitable for use as albumin-binding compounds include, without limitation, RG 19, and Cibacrom Blue 3GA (CB 3 GA).
In some embodiments, the results of lipoprotein analyses are reported in an analysis report. “Analysis report” refers in the context of lipoprotein and other lipid analyses contemplated by the invention to a report provided, for example to a clinician, other health care provider, epidemiologist, and the like, which report includes the results of analysis of a biological specimen, for example a plasma specimen, from an individual. Analysis reports can be presented in printed or electronic form, or in any form convenient for analysis, review and/or archiving of the data therein, as known in the art. An analysis report may include identifying information about the individual subject of the report, including without limitation name, address, gender, identification information (e.g., social security number, insurance numbers), and the like. An analysis report may include biochemical characterization of the lipids in the sample, for example without limitation triglycerides, total cholesterol, LDL cholesterol, and/or HDL cholesterol, and the like, as known in the art and/or described herein. An analysis report may further include characterization of lipoproteins, and references ranges therefore, conducted on samples prepared by the methods provided herein. The term “reference range” and like terms refer to concentrations of components of biological samples known in the art to reflect typical normal observed ranges in a population of individuals. Exemplary characterization of lipoproteins in an analysis report may include the concentrations of non-HDL lipoproteins and Lp(a) determined by ion mobility. Further exemplary characterization of lipoproteins, determined for example by ion mobility analyses conducted on samples prepared by methods of the invention, include the concentration and reference range for VLDL, IDL, Lp(a), LDL and HDL, and subclasses thereof. An analysis report may further include lipoprotein size distribution, obtaining for example by ion mobility analysis, of a sample prepared by methods of the invention. Entries included in an exemplary analysis report are provided in Example 7.
To assess whether HDL (Apo A1) was preferentially lost in procedures employing D2O, three samples as shown in FIG. 3 (i.e., 749, 1043, 14: arbitrary and unique patient identification numbers) were subjected to lipoprotein isolation employing D2O together with RGD/DS solution (7.5/2.5 mg/mL, respectively) to remove albumin. Samples were each prepared in replicates of six. The isolated individual top 100 uL were each analyzed for content of Apo A1 (HDL), Apo B (LDL, IDL, VLDL) and total cholesterol (TC). Plasma or serum apolipoproteins AI and B were measured by standardized ELISA using commercially available monoclonal capture antibodies (Biodesign International, Saco, Minn.) and anti-human goat polyclonal detection antibodies, purified and biotinylated, (International Immunology Corp., Murrieta, Calif.) in a non-competitive sandwich-style immunoassay. Concentration was measured by addition of streptavidin conjugated peroxidase followed by color development using ortho-phenyline-diamine. Lipoprotein calibrators were standardized using CDC #1883 serum reference material (Center for Disease Control, Atlanta, Ga.) and pooled reference sera (Northwest Lipid Research Clinic, Seattle, Wash.). Total cholesterol was measured using commercially available assay kit reagents (Bayer Health Care, Tarrytown, N.Y.) according to manufacturers instructions and modified for analysis of 25 μl serum or plasma plus 200 μl cholesterol reagent per microtiter plate well. Standards, controls, samples and reagent background were measured after color development using a microtiter plate reader. The results (FIG. 3) show the mean recovery of each sample compared to the total present in each serum. Without wishing to be bound by any theory, the purification procedure did not result in preferential loss of HDL, as judged by equivalent recovery of Apo A1 and Apo B.
In a typical production procedure, sample(s) together with controls, one sample known to be LDL pattern A (control A) and one sample known to be pattern B (control B) as known in the art, are placed on the Perkin Elmer JANUS multiprobe. 30 uL of controls and sample(s) are transferred to a separate tube and mixed, and 120 uL of the RG19 dextran, DS, EDTA solution is added. The tubes are then transferred to ice for a 15-minute incubation. Following the 15 min incubation the tubes are returned to the multiprobe. In the meantime, centrifuge tubes have had two 4 mm beads added to them, and these are then placed on the multiprobe where 120 uL of D2O is added to each centrifuge tube. Controls and sample(s) are then overlaid on the D2O by the multiprobe before being transferred to the ultracentrifuge rotor (Ti 42.2). Samples are then spun for 135 min at 10 C at 223,000×G (42,000 rpm). Following centrifugation, the centrifuge tubes are removed carefully and placed on the multiprobe where the top 85 uL (+/−5 uL) is removed to a separate tube. Once all samples are collected the multiprobe makes two dilutions for each control and sample. One dilution is a final dilution of 1:200 with ammonium acetate solution containing 5 ug/mL DS; the second is a 1:800 dilution with just ammonium acetate solution. The two dilutions are then run on the ion mobility instrument. Following analysis the particle numbers are converted to nmol/L using conversions well known in the art. The data from the HDL run (1:800) and the larger lipoproteins (1:200) are combined and reported together with the biochemical data from aliquots 1 and 2. The profile of the lipoproteins is also reported as well as the total LDL particle concentration and the LDL peak particle size, which is used to determine the LDL phenotype. An exemplary assessment report resulting from combining these data is provided in Table 2 (numerical representation) and FIG. 7 (graphical representation of lipoprotein profile).
Co Li- Co Tot. Stop
HDL mg/ gand mg/ AF488 Vol Soln
Subfr. ml μl mg ml μl mg μl μl
1—Add HDL subfr to glass vial with mag-stir bar
2—While stirring at rm. temp., add AF488 volume to ligand slowly.
3—Incubate mixture for 1 hour w/continuous stirring.
4—Add Stop Soln (1.5 M Tris, pH 8.0). Incubate at rm temp 30 min.
5—Dialyze labeled HDL Subfrs to 20 mM Tris. 150 mM NaCl, 0.27 mM EDTA, pH8 [in cold box, protect from light] vs. 1 liter overnite, and 2×1 L dialysate volume changes.
Region variable region, nm Functional correction
2 7 <= d < 7.1 y2 = k2 * e(−2.56 * 7.1) Eqn. (5)
3 7.1 <= d < 8.5 y3 = k3 * e(−2.56 * d) Eqn. (6)
4 8.5 <= d < 15  Empirical (from spiked albumin data)
y′=y*((d−lowerlimit)*2*dimer+(upperlimit−d)*2) (7)
In one embodiment, the measured values are compared to empirically determined ranges to perform a diagnosis based on a patient's serum or plasma values falling within or outside a range. The table below illustrates one exemplary set of ranges for such a diagnosis:
Female 475-4224 903-3779 384-1616
Male 613-3344 1174-3744 169-1153
Female 33-129 82-442 91-574 51-186 272-1189
Male 38-164 136-627 200-596 48-164 508-1279
LDL Paricle Size (A)
Female 215.4-232.9
Male 212.3-230.9
Female 11-48 10-38
Male 12-59 11-41
Female 5.8-26.6 1.0-5.7 0.2-1.8
Male 5.0-23.0 1.1-7.3 0.2-2.5
Ion mobility spectrometry provides a way to measure the size distribution of nanoparticles based on gas-phase particle electrical mobility. This methodology was adapted for measuring the size distribution of lipoprotein particles. The method was automated and generated profiles of particle number and particle mass versus particle diameter in about one minute. Lipoproteins are first enriched (plasma protein removal) by ultracentrifugation and then diluted in a volatile buffer and electrosprayed. A charge neutralization process leaves a well-characterized fraction of the particles with a single charge. The charged particles are drawn through a Differential Mobility Analyzer (DMA), which allows particles of a narrow size to pass to a particle counter as a function of a voltage applied to the DMA. By scanning the applied voltage, particle number distributions are obtained for HDL, LDL, IDL and VLDL. The measurements are based on first principles and do not need to be calibrated with respect to particle size. Particle number distributions are converted into particle mass distributions. Using this method, the intra-assay variation for LDL diameter was <0.6%, for concentration, <10% for HDL and LDL and <15% for IDL and VLDL. The inter-assay reproducibility was <1.0% for LDL particle size, and for concentration, <15% for HDL and LDL and <20% for IDL and <25% for VLDL. The table below shows the summary data, expressed as mean and SD, used to generate reference ranges for the individual lipoprotein fractions. A total of 259 healthy individuals (191 F, 68 M) who met the current NCEP ATP III criteria for optimal lipid/lipoprotein levels: total cholesterol (chol)<200, LDL chol <100, HDL chol >40 (M)>50 (F), triglyceride <150 mg/dL were used in the study. The results show the expected difference between genders, males having higher concentrations of smaller LDL particles and females having increased HDL 2b.
Lipoprotein Mean SD P males vs
1. A method for purifying lipoproteins for differential charged particle mobility analysis, said method comprising:
a) incubating a solution comprising lipoproteins, non-lipoproteins, dextran sulfate and a solid support comprising a paramagnetic particle, under conditions for said lipoproteins to bind to said solid support;
b) isolating said solid support from the solution thereby separating said lipoproteins from said non-lipoproteins; and
c) releasing said lipoproteins from said solid support, wherein said released lipoproteins are suitable for differential charged particle mobility analysis that determines size distribution of said lipoproteins;
and d) subjecting said lipoproteins to differential charged particle mobility analysis
said lipoproteins comprise HDL and one or more selected from the group consisting of LDL, Lp(a), IDL and VLDL; and
said method does not include centrifugation.
2. The method according to claim 1, wherein said solid support comprises a bead.
3. The method according to claim 1, wherein said solid support comprises a lipoprotein-capture ligand capable of binding lipoproteins.
4. The method according to claim 3, wherein said lipoprotein-capture ligand is selected from the group consisting of an aptamer and an antibody.
5. The method according to claim 1, wherein subjecting said lipoprotein to differential charged particle mobility analysis comprises:
determining a differential mobility particle size distribution in one or more regions of particle sizes for said lipoproteins;
subtracting contribution to the particle size distribution of a non-lipoprotein reagent or a non-lipoprotein sample material to obtain a lipoprotein particle size distribution; and
outputting the lipoprotein particle size distribution to a display, a printer or a memory.
6. The method according to claim 5, wherein the determining a particle size distribution includes determining a best fit for the one or more regions.
7. The method according to claim 6 wherein the best fit is of the form:
y 1 =k 1 *e (−0.7*d);
where y1 is a contribution to the measured differential mobility size distribution, k1 is an empirical constant of the fit, and d is particle diameter;
wherein the determining a best fit includes calculating a value for k1.
8. The method according to claim 5, wherein the subtracting includes applying a theoretical curve representing particle size distribution of the non-lipoprotein reagent or the non-lipoprotein sample material.
9. The method according to claim 5, wherein the non-lipoprotein reagent is Reactive Green 19 conjugated with dextran (RGD).
10. The method according to claim 5, wherein the non-lipoprotein sample material is albumin.
11. A method for purifying lipoproteins for differential charged particle mobility analysis, said method comprising:
b) isolating said solid support from the solution thereby separating said lipoproteins from said non-lipoproteins;
c) releasing said lipoproteins from said solid support;
d) subjecting said lipoproteins to differential charged particle mobility analysis that comprises:
determining a differential mobility particle size distribution in one or more regions of particle sizes for said lipoproteins; and
outputting the lipoprotein particle size distribution to a display, a printer or a memory;
said lipoproteins comprise HDL and one or more selected from the group consisting of LDL, Lp(a), IDL and VLDL, and
the determining a differential mobility particle size distribution includes determining a best fit for the one or more regions.
12. The method according to claim 11, wherein said method does not include centrifugation.
13. The method according to claim 11, wherein said solid support comprises a bead.
14. The method according to claim 11, wherein said solid support comprises a lipoprotein-capture ligand capable of binding lipoproteins.
15. The method according to claim 14, wherein said lipoprotein-capture ligand is selected from the group consisting of an aptamer and an antibody.
16. The method according to claim 11 wherein the best fit is of the form:
17. The method according to claim 11, wherein the subtracting includes applying a theoretical curve representing particle size distribution of the non-lipoprotein reagent or the non-lipoprotein sample material.
18. The method according to claim 11, wherein the non-lipoprotein reagent is Reactive Green 19 conjugated with dextran (RGD).
19. The method according to claim 11, wherein the non-lipoprotein sample material is albumin.
US14/226,089 2007-06-08 2014-03-26 Lipoprotein analysis by differential charged-particle mobility Active US9046539B2 (en)
US11/760,672 US8247235B2 (en) 2007-06-08 2007-06-08 Lipoprotein analysis by differential charged-particle mobility
US13/589,404 US8709818B2 (en) 2007-06-08 2012-08-20 Lipoprotein analysis by differential charged-particle mobility
US14/226,089 US9046539B2 (en) 2007-06-08 2014-03-26 Lipoprotein analysis by differential charged-particle mobility
US14/726,802 US9791464B2 (en) 2007-06-08 2015-06-01 Lipoprotein analysis by differential charged-particle mobility
US15/711,778 US20180011117A1 (en) 2007-06-08 2017-09-21 Lipoprotein analysis by differential charged-particle mobility
US16/281,584 US20190187160A1 (en) 2007-06-08 2019-02-21 Lipoprotein analysis by differential charged-particle mobility
US13/589,404 Continuation US8709818B2 (en) 2007-06-08 2012-08-20 Lipoprotein analysis by differential charged-particle mobility
US14/726,802 Continuation US9791464B2 (en) 2007-06-08 2015-06-01 Lipoprotein analysis by differential charged-particle mobility
US20140287530A1 US20140287530A1 (en) 2014-09-25
US9046539B2 true US9046539B2 (en) 2015-06-02
ID=40096232
US11/760,672 Active 2030-09-24 US8247235B2 (en) 2007-06-08 2007-06-08 Lipoprotein analysis by differential charged-particle mobility
US13/589,404 Active US8709818B2 (en) 2007-06-08 2012-08-20 Lipoprotein analysis by differential charged-particle mobility
US14/226,089 Active US9046539B2 (en) 2007-06-08 2014-03-26 Lipoprotein analysis by differential charged-particle mobility
US14/726,802 Active 2027-08-21 US9791464B2 (en) 2007-06-08 2015-06-01 Lipoprotein analysis by differential charged-particle mobility
US15/711,778 Abandoned US20180011117A1 (en) 2007-06-08 2017-09-21 Lipoprotein analysis by differential charged-particle mobility
US16/281,584 Pending US20190187160A1 (en) 2007-06-08 2019-02-21 Lipoprotein analysis by differential charged-particle mobility
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