US20070049732A1 - Ultra-high yield intravenous immune globulin preparation - Google Patents

Ultra-high yield intravenous immune globulin preparation Download PDF

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Publication number
US20070049732A1
US20070049732A1 US11/217,956 US21795605A US2007049732A1 US 20070049732 A1 US20070049732 A1 US 20070049732A1 US 21795605 A US21795605 A US 21795605A US 2007049732 A1 US2007049732 A1 US 2007049732A1
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blood
product
based material
solution
sodium citrate
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US11/217,956
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Eugene Zurlo
Dennis Curtin
Allan Louderback
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Plasma Technologies LLC
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Plasma Technologies LLC
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Priority to US11/217,956 priority Critical patent/US20070049732A1/en
Assigned to PLASMA TECHNOLOGIES, LLC reassignment PLASMA TECHNOLOGIES, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LOUDERBACK, ALLAN L., CURTIN, DENNIS, ZURLO, EUGENE J.
Priority to US11/232,527 priority patent/US7879331B2/en
Priority to US11/358,431 priority patent/US7879332B2/en
Priority to PCT/US2006/030465 priority patent/WO2007030244A2/en
Priority to AT06800767T priority patent/ATE541858T1/de
Priority to AU2006287833A priority patent/AU2006287833B2/en
Priority to EP06800767A priority patent/EP1928915B1/en
Priority to JP2008529047A priority patent/JP5178518B2/ja
Priority to ES06800767T priority patent/ES2384930T3/es
Priority to CN200680032267.2A priority patent/CN101528776B/zh
Priority to CA2621025A priority patent/CA2621025C/en
Publication of US20070049732A1 publication Critical patent/US20070049732A1/en
Priority to US12/134,504 priority patent/US20080242844A1/en
Priority to US12/973,218 priority patent/US8293242B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/76—Albumins
    • C07K14/765—Serum albumin, e.g. HSA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • This invention relates generally to methods for immune serum globulin purification, and, more particularly, to methods for alcohol-free separation of immune globulin from blood plasma or other blood based material.
  • Chromatography separates plasma proteins by specifically targeting unique characteristics of each, including molecular size (gel filtration), charge (ion exchange chromatography), and known interactions with specific molecules (affinity chromatography).
  • Shanbrom Two U.S. Patent Applications, filed by Edward Shanbrom, having Application Numbers 20030022149 (Shanbrom '149) and 20030129167 (Shanbrom '167) filed Jan. 30, 2003 and Jul. 10, 2003, respectively, teach of use of carboxylic salts (e.g., trisodium citrate) as an agent for enhancing formation of a cryoprecititate from plasma.
  • carboxylic salts e.g., trisodium citrate
  • the method(s) of Shanbrom generally involve trisodium citrate and other citrate salts as agents for enhancing production of blood clotting factors from cryoprecipitate.
  • Shanbrom '149 teaches in paragraph 0009 that “It is an object of the present invention to provide enhanced yields of cryoprecipitate.” Shanbrom also teaches, in paragraph 0011, that carboxylic acids are effective agents for enhancing the production of blood clotting factors from the cryoprecipitate. Shanbrom '149 notes that the addition of citrate to plasma, especially at concentrations between two and ten percent, by weight, does not appreciably denature labile proteins. Moreover, it is noted in Shanbrom '149 that citrate potentiates or enhances the killing of microorganisms by heat treatment.
  • Shanbrom '167 notes in paragraph 0015 that “Not only does added citrate increase the amount of cryoprecipitate, it simplifies the process by decreasing the requirement for freezing” plasma in order to harvest cryoprecipitate.
  • Shanbrom clearly teaches use of production of a cryoprecipitate for the purpose of fractionating products from the cryoprecipitate through the use of trisodium citrate in concentrations of two to ten percent.
  • Shanbrom '149 and '167 deal directly with extracting labile coagulation products from a cryoprecipitate formed through use of citrate compounds, particularly trisodium citrate, and with killing microorganisms in the cryoprecipitate using the citrate compounds
  • the instant invention deals directly with extracting non-labile products (e.g., albumin, gamma globulin and alpha-1-antitrypsin) from a supernatant formed through use of citrate compounds.
  • non-labile products e.g., albumin, gamma globulin and alpha-1-antitrypsin
  • this instant invention provides novel and effective methods of isolating gamma globulin from plasma and formulating it into an intravenous injectable preparation. Accordingly, this invention, which may be defined to be “an ultra-high yield intravenous immune globulin preparation,” achieves higher yields of a superior quality gamma globulin by directly and expeditiously separating the gamma globulin from the plasma by means of a non-denaturing precipitant, sodium citrate.
  • the inventive process is for fractionating blood-based products to produce a useful, non-denatured immunoglobulin (IgG) product which involves the following critical steps:
  • the first volume utilizes a fifty percent sodium citrate solution.
  • the supernatant and residual paste should have a range of eleven to thirteen percent, and preferably should approximate a twelve percent concentration.
  • the residual paste may be further fractionated into blood factors including VIII, IX, von Willebrand and fibrinogen. Separation of the products may be accomplished by centrifuging or existing methods which are well known in chemistry art.
  • the second volume utilizes addition of another fifty percent sodium citrate solution.
  • the second product is a paste and the second residual is a supernatant, both having a range of concentration of approximately twenty-one to twenty-three percent sodium citrate, which should approximate twenty-two percent.
  • the residual (supernatant) may be further processed into a group of components comprising albumin and alpha-1-antitrypsin. The products may be separated by centrifuging, filtering or other methods which are well-known in the chemistry art.
  • step (c) it is preferred to dilute the paste product with water having approximately four times the weight of the paste product, although other volumes of water may be judiciously selected within the scope of the invention.
  • a diafiltration system with a 30 KD filtering membrane may be used to separate the sodium citrate and excess water from the resulting product to permit further processing on an industrial scale. Note, that such filtering is made facile and possible by extracting euglobulins from the supernatant in step (a).
  • euglobulins are defined to be those globulins which are insoluble in water, but are soluble in saline solutions.
  • euglobulins are not removed from a solution and if the ionic strength of that solution is lowered towards deionized water (e.g., in the case of the instant invention), euglobulins foul a diafiltration system, thereby rendering it unuseable.
  • albumin and alpha-1-antitrypsin are subsequently removed from the remaining proteins by methods available from Cohn or others.
  • the process enables the separation of gamma globulin without exposing it to the denaturing effects of ethanol used in the Cohn process, hence leaving the gamma globulin in a native state.
  • the denaturing effects of alcohol include the formation of polymers, aggregates and fragments of the gamma globulin molecule.
  • sodium citrate stabilizes the plasma while bringing about precipitation of substantially all of the coagulation proteins, thus preventing the generation of enzyme activators and proteolytic enzymes.
  • the process of the instant invention employs high concentrations of sodium citrate combined with its subsequent removal from the gamma globulin concentrate by means of diafiltration, a technique which became practical on an industrial scale in the 1980's.
  • Final purification of the resulting gamma globulin is then practically and effectively achieved through the use of well-established chromatographic purification techniques.
  • the invention reduces production costs as a result of higher yields, fewer fractionation steps, shorter overall processing time, lower energy costs, and lower chemical costs.
  • Capital costs are less because of reduced space requirements, reduced work-in-process, reduced processing time, and elimination of the explosion proof environments required for ethanol processing.
  • FIG. 1 is a flow diagram of a critical set of initial steps associated with the process according to the instant invention.
  • FIG. 2 is a flow diagram disclosing a series of steps which immediately follow the steps seen in FIG. 1 .
  • FIG. 3 is a flow diagram disclosing those procedural steps which immediately follow the steps seen in FIG. 2 .
  • FIG. 4 is a flow diagram disclosing steps which immediately follow the steps seen in FIG. 3 to provide a useful product.
  • each rectangular box is used to illustrate a procedural step; each diamond is used to demonstrate a separation step; each elliptical cylinder designates a product resulting from a preceding procedural or separation step; and each circle is used to identify either a starting point or an off-sheet continuation path point.
  • FIG. 1 wherein an initial portion 10 - 1 of an preferred IgG process flow path, generally numbered 10 , is seen.
  • a volume of plasma 30 to be processed is selected for processing.
  • plasma 30 is used by example in this description of an illustrated embodiment, other blood-based products may be processed within the scope of the instant invention.
  • selected frozen plasma 30 is warmed to approximately five degrees Centigrade to form prepared plasma 50 . While five degrees is the target plasma 30 process temperature, which should be maintained throughout the following steps in process 10 , a temperature range between limits of two to eight degrees may be held within the scope of the instant invention. Plasma 30 may be used directly if not selected in a frozen state (e.g., thawed during the process of removing a cryogenic precipitate by customary methods).
  • a batch of sodium citrate solution is made per procedure 52 wherein a fifty percent sodium citrate solution is prepared by stirring five hundred grams of sodium citrate into six hundred milliliters of purified water. Stirring time should be thirty to sixty minutes or, alternately, until the sodium citrate is dissolved. At this point, dilute the mixture with pure water to one thousand milliliters. Add a 50% citric acid solution to the mixture until a pH of 7.0 is reached.
  • a volume of fractionation solution to be added to plasma 30 is calculated. It is a goal that the concentration of the sodium citrate fractionation solution should be twelve percent. Also the pH of the fractionation solution should be approximately 7.0. If necessary, adjust the pH to 7.0.
  • procedure 54 over a period of approximately five minutes, add the prepared sodium citrate fractionation solution (which may be at room temperature [i.e. approximately twenty degrees Centigrade]) to plasma 30 (which has a starting temperature of five degrees Centigrade). Gently stir while adding the sodium citrate solution. Once the sodium citrate solution is completely added to plasma 30 , continue gently stirring the resulting slurry for approximately sixty minutes while reducing the slurry temperature to within a range of two to eight degrees centigrade. (The slurry should maintain pH at approximately 7.0 to 7.1.)
  • centrifuge Upon completion of procedure 54 , centrifuge as procedure 56 . It is recommended that a flow-through centrifuge (e.g., a Westphalia Centrifuge) be used to separate component parts of the slurry into a supernatant liquid 60 and a paste 62 by normal procedures for those skilled in the art, while maintaining temperature of the slurry in the range of two to eight degrees Centigrade.
  • a flow-through centrifuge e.g., a Westphalia Centrifuge
  • paste 62 may be further processed to recover blood factors, including Factors VIII, IX, von Willebrand and fibrinogen.
  • process step 64 For the second fractionation phase, perform process step 64 which adds additional sodium citrate fractionation solution to supernatant liquid 60 . Enough fifty percent sodium citrate is added to liquid 60 to increase concentration of sodium citrate from twelve percent to twenty-two percent.
  • C e (( V 60 *C 60 )+( V x *C 0.50 ))/( V 60 +V x )
  • C e is the desired end concentration of sodium citrate
  • V 60 is the volume of supernatant liquid 60
  • C 60 is sodium citrate concentration in supernatant liquid 60
  • V x is volume of fifty percent sodium citrate to be added
  • C 0.50 is concentration of fifty percent sodium citrate (i.e. 0.50).
  • V x V 60 *( C e ⁇ C 60 )/( C 0.50 ⁇ C e )
  • paste 70 includes IgG, other serum proteins and sodium citrate.
  • the sodium citrate must be removed from paste 70 to permit IgG to be isolated by ion exchange chromatography.
  • paste 70 is liquified using purified water (of about four times the volume of paste 70 ) as step 90 .
  • Product of step 90 is an IgG rich solution 100 .
  • Initial conductivity of solution 100 is approximately 20 milliSiemens/centimeter (mS/cm).
  • Step 102 Removal of sodium citrate is accomplished by continuous diafiltration using purified water as a solvent in step 102 which separates solution 100 into removed sodium citrate 110 and desalted IgG retentate 112 .
  • Completion of step 102 is indicated when the conductivity of retentate 112 is reduced to 500-900 microSiemens/centimeter (uS/cm).
  • a Millipore (or comparable) diafiltration system equipped with 30 KD cut-off membranes may be employed.
  • Viral inactivation of IgG rich retentate 112 may be accomplished as a double viral inactivation step involving a first solvent/detergent (S/D) method, followed by an augmented S/D method.
  • the first method employs raising the temperature of retentate 112 to approximately 27° Centigrade (temperature may range from 24-30° Centigrade).
  • a sufficient volume of Triton X-100 or Tween 80 is then added to make a one percent solution and sufficient Tri-N-Butyl Phosphate to make a three tenths of one percent solution to make a first S/D added mixture.
  • the first method continues by incubating the first S/D added mixture at 27° Centigrade for three hours during which time lipid enveloped viruses are inactivated. From this point, procedures currently available, inactivation and fractionation processes may be employed. However, a currently preferred process is hereafter provided for completeness.
  • a S/D concentrate may be made as follows:
  • an “augmented” concentrate may be made as follows:
  • Step 120 is completed by cooling the processed augmented mixture to a temperature of two to eight degrees Centigrade. So cooled, the augmented mixture becomes IgG virus inactivated (VI) solution 122 .
  • viruses may be removed by other methods (e.g., chromatography, nanofiltration, pasteurization), if desired.
  • Step 124 involves use of column chromatography to remove viral inactivation chemicals. Such may be accomplished by the following sub-steps:
  • a volume of two percent solution of sodium chloride is prepared.
  • Application of the sodium chloride is used to effect release of attached IgG from resin particles.
  • a two percent solution is made by mixing 20 grams of sodium chloride into one liter of deionized water.
  • Sufficient volume of two percent sodium chloride solution should be made to equal about ten times the volume of the resin column.
  • step 134 add the sodium chloride solution to the column, collecting effluent from the column. Concurrently, measure optical density of the effluent solution at 280 nanometers using a spectrophotometer with a one centimeter silica cuvette. Resultant optical density (OD) will be found to suddenly increase as IgG is uncoupled from the resin and delivered into the effluent. Collect all high OD measured solution. When the OD of the effluent drops to a lower (normal) range, cease collecting the solution. Resulting solution is IgG solution 140 . Note that a high OD is indicative of protein content in solution, and that solution 140 may contain small amounts of IgM and IgA, which requires further removal. In addition solution 140 contains sodium chloride which must be removed before any pure IgG can be isolated.
  • Sodium chloride is preferably removed from solution 140 by continuous diafiltration employing a diafiltration system. Such may consist of a Millipore (or comparable) diafiltration system equipped with 30 KD cut-off membranes.
  • the diafiltration solvent is purified water.
  • initial conductivity of solution 140 is approximately fifty milliSiemens/centimeter (mS/cm).
  • conductivity is reduced to 500-900 microSiemens/centimeter (uS/cm).
  • the products of diafiltration are an IgG rich retentate 160 and removed sodium chloride 164 . It is recommended that serum electrophoresis be performed at this step in the process to quantitate protein content in retentate 160 .
  • Step 166 is a final step for purifying IgG rich retentate 160 .
  • step 166 it is preferred to set up a short, wide resin column with Toyopearl QAE-550C resin.
  • Such resin provides a strong anionic exchange for capturing other proteins in IgG rich retentate 160 , while permitting IgG in solution to flow through the column. It is important that conductivity of retentate 160 be in a range of 100 to 900 microSeimens/centimeter, and preferably, within a range of 400 to 600 microSeimens/centimeter.
  • IgG in retentate 160 will pass through the resin column in Step 166 without binding, while other proteins, including IgM and IgA, will bind to resin in the column and thus be removed from solution. In this manner, any contaminating residual proteins 170 are effectively separated from a purified IgG solution 172 .
  • IgG solution 172 be collected and the OD measured for a target 280 nm. Collect the high OD effluent solutions. When the measured OD drops, cease collecting. The pooled solution is relatively dilute.
  • the pooled solution is concentrated using step 180 via ultrafiltration.
  • a hollow fiber filter may be used, or a Millipore ultrafiltration system (Pellicon) or equivalent, (10 K to 30 K dalton retentation) to concentrate to a twelve percent IgG solution 182 .
  • Excess water 184 is removed in the process of step 180 .
  • the resulting twelve percent concentrate should have only a trace amount of sodium chloride and the pH should be approximately seven.
  • Conductivity should measure about 100 to 900 microSiemens/centimeter.
  • step 190 a maltose or sorbitol solution to dilute the twelve percent solution to exactly ten percent.
  • the final ten percent solution (IgG solution 192 ) should contain approximately five percent maltose or sorbitol (whichever is used).
  • nanofiltration may be performed by passing the ten percent solution 192 through a virus retaining membrane (step 200 ) to produce a nanofiltered concentrate 202 .
  • Resulting sterile solution 232 may be filled into vials per standard procedures in step 240 to produce a lot 242 of vials of solution 232 .
  • final testing and inspection of lot 242 may be made in step 244 in cooperation with step 246 to produce a lot 250 of validated vials of solution 232 , with any discard 252 being removed therefrom.
  • the gels were electrophoresed for twenty-five minutes at 100 VDC at a pH of 8.6 and later stained with a Paragon blue stain.
  • the Appraise densitometer was used to scan the stain-dried gels at a wavelength of 600 nanometers twice for each gel slit (ten gel slits per gel were used).
  • An average graphic representation of the distribution of five different protein fractions, based upon density of attached dye as well as a numeric presentation of each fraction was derived. The numeric presentation was based upon a computer analysis of peaks and valleys of generated graphs at selected locations within the gel pattern as occurred between the anode and cathode on each gel. Presentation values were totaled and dye percentage was divided by the total dye amount to provide a percentage for evaluation. Note that the grand total, summing each individual blood fraction always equals one hundred percent.
  • Plasma i.e., plasma 50
  • Plasma 50 Plasma from the pool was treated with the addition of a volume of fifty percent sodium citrate to a volume of plasma to make a twelve percent solution of sodium citrate (step 54 ). This mixture was stirred for sixty minutes at two to eight degrees centigrade and was then centrifuged (Step 56 ) for sixty minutes at two to eight degrees centigrade. The resulting supernatant solution 60 was measured. The remaining paste 62 was weighed and put into solution by addition of deionized water.
  • step 64 sufficient fifty percent solution sodium citrate was added to supernatant 60 (step 64 ) to obtain a final mixture that contained twenty-two percent sodium citrate. This solution was also stirred for sixty minutes at two to eight degrees centigrade. After centrifuging (see step 66 ) for sixty minutes at two to eight degrees centigrade, the resulting supernatant solution 72 was measured. The remaining paste 70 was weighed and put into solution (step 90 ) by the addition of deionized water (four times weight of paste 70 in milliliters) to form IgG rich solution 100 .
  • the twenty-two percent paste solution contained the gamma globulin of interest for further fractionating to produce intravenous gamma globulin for injection. Note also that, in step 90 , time should be allowed for the paste to solvate prior to performing electrophoresis. In the experimental process, a plasma fraction between twelve percent and twenty-two percent sodium citrate was selectively isolated out for use in this isolation procedure.
  • a Pellicon unit was selected to diafilter solution 100 .
  • the volume of solution 100 was required to diafilter the sodium citrate and bring conductivity of the resulting solution down to a range between 400 and 800 microSiemens/centimeter (uS/cm), before performing any column work.
  • the desalted protein solution 112 was treated electrophoretically to determine any changes or losses as a result of diafiltration step 102 . Because sodium citrate was removed, protein movement in the electrophoretic pattern was changed somewhat through lack of interference with a contained salt. The resulting pattern was somewhat longer than a high salt concentration pattern.
  • the sterile treated solution was transferred to an ion exchange column loaded with Toyopearl CM-650C resin.
  • the resin adsorbed gamma globulin and allowed all of the other proteins present in solution to flow out in effluent from the column.
  • effluent solution was measured at 280 nanometers to determine when all free proteins and sterilants had been transported through the column.
  • the column was washed with a two times volume of deionized purified water to assure that the effluent has a very low measured optical density at 280 nanometers.
  • a two percent solution of sodium chloride was then dispensed onto the top of the column and allowed to percolate through the column.
  • Gamma globulin which was adsorbed by resin particles was freed to flow out of the column into a receiving vessel.
  • beta globulin 1.9% may be the result of an application spot when applying solution to gel.
  • the two percent sodium chloride solution contained the gamma globulin (IgG) and, perhaps, with larger pools of plasma, may contain some IgA and IgM globulins which should be removed.
  • the two percent sodium chloride solution was therefore diafiltered to remove the sodium chloride for a next column treatment. Diafilitration was again performed by passing the solution though a Pellicon unit whereby the salt was removed, yielding a final product which had a conductivity of 400 to 800 microSeimens/centimeter (uS/cm). Note that it likely takes about six volumes of dionized purified water to diafilter the two percent solution.
  • a column was filled with Toyopearl 560-C resin and the desalted solution was added to the top of the column and allowed to slowly percolate through the column.
  • gamma globulin flowed right through the resin and all other proteins attached to the resin (e.g., IgA and IgM) to yield a final effluent from the column (solution 172 ) that was 100% gamma globulin in an aqueous base.

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Priority Applications (13)

Application Number Priority Date Filing Date Title
US11/217,956 US20070049732A1 (en) 2005-09-01 2005-09-01 Ultra-high yield intravenous immune globulin preparation
US11/232,527 US7879331B2 (en) 2005-09-01 2005-09-22 Ultra-high yield intravenous immune globulin preparation
US11/358,431 US7879332B2 (en) 2005-09-01 2006-02-21 Ultra-high yield intravenous immune globulin preparation
CA2621025A CA2621025C (en) 2005-09-01 2006-08-04 An ultra-high yield intravenous immune globulin preparation
EP06800767A EP1928915B1 (en) 2005-09-01 2006-08-04 An ultra-high yield intravenous immune globulin preparation
AT06800767T ATE541858T1 (de) 2005-09-01 2006-08-04 Präparation von intravenösem immunglobulin mit ultrahoher ausbeute
AU2006287833A AU2006287833B2 (en) 2005-09-01 2006-08-04 An ultra-high yield intravenous immune globulin preparation
PCT/US2006/030465 WO2007030244A2 (en) 2005-09-01 2006-08-04 An ultra-high yield intravenous immune globulin preparation
JP2008529047A JP5178518B2 (ja) 2005-09-01 2006-08-04 超高収率静注免疫グロブリン製剤
ES06800767T ES2384930T3 (es) 2005-09-01 2006-08-04 Preparación de inmunoglobulina intravenosa de rendimiento ultra-alto
CN200680032267.2A CN101528776B (zh) 2005-09-01 2006-08-04 静脉注射免疫球蛋白制剂的生产方法
US12/134,504 US20080242844A1 (en) 2005-09-01 2008-06-06 Ultra-high Yield Intravenous Immune Globulin Preparation
US12/973,218 US8293242B2 (en) 2005-09-01 2010-12-20 Ultra-high yield of alpha-1-anti-trypsin

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US20180306772A1 (en) * 2015-10-15 2018-10-25 Plasma Technologies, Llc Methods for extracting proteins from blood plasma
US10815270B1 (en) * 2019-09-20 2020-10-27 Plasma Technologies, Llc Compositions and methods for high efficiency protein precipitation
US10836790B1 (en) * 2019-09-20 2020-11-17 Plasma Technologies, Llc Therapeutic protein compositions and methods
US11028125B2 (en) 2016-02-03 2021-06-08 Plasma Technologies, Llc Methods for extracting proteins from a blood-based material
CN115369104A (zh) * 2022-09-27 2022-11-22 四川新川义生物科技有限责任公司 一种精制胃蛋白酶的方法

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EP1909831A4 (en) 2005-06-14 2013-02-20 Amgen Inc SELF-BUFFING PROTEIN FORMULATIONS
WO2009129226A1 (en) 2008-04-15 2009-10-22 Talecris Biotherapeutics, Inc. Two-stage ultrafiltration/diafiltration
WO2010148117A1 (en) 2009-06-17 2010-12-23 Scantibodies Laboratory, Inc. Therapeutic and diagnostic affinity purified specific polyclonal antibodies
IT1397061B1 (it) 2009-12-28 2012-12-28 Kedrion Spa Nuovo processo di purificazione su scala industriale di gammaglobuline da plasma umano per uso industriale.
AU2012284122B2 (en) 2011-07-18 2017-06-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods and compositions for inhibiting polyomavirus-associated pathology
US9696305B2 (en) 2011-10-31 2017-07-04 Bloodworks Antibody response phenotyping
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ATE541858T1 (de) 2012-02-15
JP5178518B2 (ja) 2013-04-10
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