WO2003001877A2 - Diagnostic et traitement des rejets de tissu cardiaque - Google Patents

Diagnostic et traitement des rejets de tissu cardiaque Download PDF

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Publication number
WO2003001877A2
WO2003001877A2 PCT/US2002/019971 US0219971W WO03001877A2 WO 2003001877 A2 WO2003001877 A2 WO 2003001877A2 US 0219971 W US0219971 W US 0219971W WO 03001877 A2 WO03001877 A2 WO 03001877A2
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Prior art keywords
blys
rejection
cardiac
expression
patient
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PCT/US2002/019971
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English (en)
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WO2003001877A3 (fr
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Daniel P. Bednarik
Kenneth B. Margulies
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Gene Logic, Inc.
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Priority to AU2002322301A priority Critical patent/AU2002322301A1/en
Publication of WO2003001877A2 publication Critical patent/WO2003001877A2/fr
Publication of WO2003001877A3 publication Critical patent/WO2003001877A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70575—NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention provides methods for the diagnosis and treatment of cardiac tissue rejection in heart transplant recipients. Specifically, the invention provides methods for measuring levels of expression of a marker gene in a patient, where elevated expression of that gene indicates that the patient is rejecting the transplanted heart. The invention also provides methods for inhibiting the expression and/or the activity of the marker gene, thereby suppressing the rejection of the transplanted heart.
  • Heart transplant patients experience on average two episodes of rejection of their transplanted hearts during the first year after the transplant, with the first 3 months being the most critical. It is apparent, therefore, that such patients need to be monitored to detect signs of transplant rejection at the earliest possible stage.
  • a method for assaying the expression of the protein BLyS (B- lymphocyte stimulator).
  • the BLyS expression is assayed at the nucleic acid level, by measurement of levels of BLyS-encoding mRNA in cardiac biopsy tissue.
  • levels of BLyS are assayed at the protein level by measuring concentration of BLyS in cardiac tissue or in peripheral blood.
  • Methods suitable for assaying BLyS include nucleic acid microarray, qPCR and ELISA.
  • BLyS expression is inhibited at the nucleic acid level using an antisense molecule that binds to BLyS-encoding mRNA and preventing translation of the message.
  • mRNA translation is inhibited using a nucleic acid molecule that promotes triplex (triple helix) formation.
  • BLyS-encoding mRNA may also be targeted using ribozymes or RNAi.
  • BLyS activity is inhibited at the protein level using an antibody, such as a human or humanized antibody, or other binding protein that binds to and inactivates BLyS.
  • BLyS activity is inhibited at the protein level using a soluble receptor molecule that sequesters BLyS.
  • the composition is administered together with an additional compound that suppresses cardiac rejection, such as cyclosporine, prednisone, azathioprine, tacrolimus or FK506, mycophenolate mofetil, OKT3, ATGAM or thymoglobulin.
  • Figure 1 shows the increased expression of BLyS in patients having allograft transplant complications (column 8605-Transplant complications) versus patients pre- and post LVAD (left ventricular assist device) or with non-failing left ventricle (LV).
  • BLyS is a member of the tumor necrosis factor (TNF) superfamily of proteins and stimulates proliferation and immunoglobulin production in plasma B cells.
  • TNF tumor necrosis factor
  • BLyS is a secreted protein expressed in activated monocytes and macrophages that induces B cell proliferation and differentiation. Moore et al., "BLyS: Member of the Tumor Necrosis Factor Family and B Lymphocyte Stimulator". Science, 285:260-263 (1999). BLyS is expressed in a 285 amino acid membrane-bound form, and also as a soluble 152 amino acid protein. Upon activation, soluble BLyS is released and can bind to at least two B-cell specific receptors, known as TACI and BCMA. Gross et al, Nature 404:995- 9 (2000). TACI is an orphan TNF receptor homologue of unknown function. Binding of BLyS to TACI activates signaling by the transcription factors NF- kappa B and ELF-1.
  • results obtained confirmed changes in regulation of known genes previously demonstrated in the literature and also identified the involvement of BLyS in the rejection of transplanted hearts.
  • a general trend of elevated BLyS expression was observed in failing transplanted hearts when compared to non- failing (non-rejecting) heart tissue.
  • levels of BLyS expression were at least about two-fold higher than in non-failing tissue, and in some cases were up to about ten-fold higher than in non-failing tissue.
  • BLyS-encoding mRNA can be obtained from a cardiac tissue biopsy of a patient under study and quantified using methods that are well known in the art.
  • BLyS-encoding mRNA also can be obtained from peripheral blood lymphocytes and levels of BLyS expression determined.
  • QPCR quantitative polymerase chain reaction
  • Antibodies against BLyS for use in ELISA analysis can be obtained using well known methods, including by hybridoma-based methodologies, or by screening of phage display libraries such as those available from Dyax (Cambridge, MA), MorphoSys (Martinsried, Germany), Biosite (San Diego CA) and Cambridge Antibody Technology (Cambridge UK).
  • Antibodies that bind to BLyS are known and are described, for example, in WO 02/02641, the disclosure of which is hereby incorporated by reference in its entirety.
  • BLyS levels can be assayed in cardiac tissue biopsy samples or in peripheral blood. In each case the levels of BLyS in the patient under study are compared to a reference level either from a patient that has not undergone heart transplant or from a patient with a transplanted heart that shows no indication of being rejected. Reference levels can be obtained from a number of healthy patients to establish a baseline level of BLyS in healthy cardiac tissue or in circulating blood. Methods for assaying BLyS levels in patients have also been reported: Zhang et al, J. Immunol.
  • BLyS expression levels in a transplant patient compared to a baseline is considered indicative of transplant rejection. More particularly, an approximately 1.5-2 fold or higher increase in BLyS expression over baseline is considered to be diagnostic of rejection. Higher levels of BLyS expression are indicative of a greater likelihood of rejection and/or a later stage of rejection.
  • the present invention also provides methods for ameliorating, reducing, inhibiting and./or preventing cardiac transplant rejection by inhibiting the expression and/or activity of BLyS.
  • Methods of inhibiting protein expression and/or function in a patient are well known in the art.
  • BLyS expression can be inhibited at the nucleic acid level using antisense reagents using well known methods. Suitable reagents are described, for example, in US Patent Nos. 5,989,912 and 5,849,902, which are hereby incorporated by reference in their entirety. Other methods for designing and manufacturing antisense reagents that are stable in the human body are well known in the art.
  • the anti-sense reagent may be antisense oligonucleotides, particularly synthetic antisense oligonucleotides having chemical modifications from native nucleic acids, or nucleic acid constructs that express such anti-sense molecules as RNA.
  • the antisense sequence is complementary to the mRNA of the targeted gene, and inhibits expression of the targeted gene products.
  • Antisense molecules inhibit gene expression through various possible mechanisms, e.g., by reducing the amount of mRNA available for translation, through activation of RNAseH or steric hindrance.
  • One or a combination of antisense molecules may be administered, where a combination may comprise multiple different sequences.
  • Antisense molecules may be produced by expression of all or a part of the target gene sequence in an appropriate vector, where the transcriptional initiation is oriented such that an antisense strand is produced as an RNA molecule.
  • the antisense molecule is a synthetic oligonucleotide.
  • Antisense oligonucleotides will generally be at least about seven, usually at least about twelve to fourteen, and more usually at least about twenty nucleotides in length.
  • Typical antisense oligonucleotides are usually not more than about five-hundred, more usually not more than about fifty, and even more usually not more than about thirty-five nucleotides in length, where the length is governed by efficiency of inhibition, specificity, including absence of cross-reactivity, and the like. It has been found that short oligonucleotides, of from seven to eight bases in length, can be strong and selective inhibitors of gene expression (see Wagner et al. (1996) Nat. Biotech. 14, 840-844).
  • a specific region or regions of the BLyS mRNA sequence is chosen to be complemented by the antisense sequence.
  • Selection of a specific sequence for the oligonucleotide may use an empirical method, where several candidate sequences are assayed for inhibition of expression of the target gene in an in vitro or animal model.
  • a combination of sequences may also be used, where several regions of the mRNA sequence are selected for antisense complementation.
  • Computer-aided methods for designing or selecting appropriate antisense oligonucleotides are known in the art.
  • Antisense oligonucleotides may be chemically synthesized by methods known in the art (see Wagner et al. (1996) Nat. Biotech. 14, 840-844). Preferred oligonucleotides are chemically modified from the native phosphodiester structure, in order to increase their intracellular stability and binding affinity. Many such modifications have been described in the literature, which alter the chemistry of the backbone, sugars or heterocyclic bases.
  • gene expression can be inhibited using methods involving triplex-forming oligonucleotides such as those described in US Patent No. 5,650,316 and references described therein, which methods are hereby incorporated by reference in their entirety.
  • Another method for blocking BLyS expression is via use of ribozymes. Methods for designing stabilized ribozymes that may be used to target specific mRNA in vivo are well known in the art. See, for example, Intracellular Ribozyme
  • RNA interference RNA interference
  • dsRNA homologous double stranded RNA
  • BLyS activity can also be blocked at the protein level using anti-BLyS antibodies, which are known in the art.
  • anti-BLyS antibodies which are known in the art.
  • inhibitory human antibodies that bind to and inhibit BLyS activity are known (see WO 02/02641 supra), or can be obtained from phage display libraries such as those described supra.
  • human anti-BLyS antibodies can be obtained using xenomouse technology such as that available from Abgenix (Fremont, CA) and Medarex (Princeton, NJ).
  • murine anti-BLyS antibodies obtained via conventional hybridoma techniques can be humanized using methods that are well known in the art. See, for example, U.S. Patents No. 5,693,762 and 5,585,089, which are hereby incorporated by reference in their entirety.
  • BLyS activity can be blocked by administering a soluble form of a BLyS binding protein such as a receptor.
  • a BLyS binding protein such as a receptor.
  • This approach has been shown to be effective in mice using a TACI-Fc fusion protein. See Marsters et al, Curr. Biol 10: 785-8, which is hereby incorporated by reference in its entirety.
  • this method would use a human BLyS receptor such as TACI in a suitable form, such as in a fusion protein with a human Fc fragment.
  • BLyS-binding polypeptides such as those described in WO 02/16411 supra, may also be used.
  • the present invention further provides compositions containing one or more agents that modulate BLyS expression or protein activity. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typical dosages comprise about 0.10 to 100.0 mg/kg body weight. The preferred dosages comprise about 0.10 to 10.0 mg/kg body weight. The most preferred dosages comprise about 0.10 to 1.0 mg/kg body weight.
  • the pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically for delivery to the site of action.
  • suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol and/or dextran.
  • the suspension may also contain stabilizers. Liposomes can also be used to encapsulate the agent for delivery into the cell.
  • the pharmaceutical formulation for systemic administration according to the invention may be formulated for enteral, parenteral or topical administration. Indeed, all three types of formulations may be used simultaneously to achieve systemic administration of the active ingredient.
  • Suitable formulations for oral administration include hard or soft gelatin capsules, pills, tablets, including coated tablets, elixirs, suspensions, syrups or inhalations and controlled release forms thereof.
  • the pharmaceutical compositions may be used alone or in combination, or in combination with other therapeutic or diagnostic agents.
  • the compositions may be co-administered along with other compounds typically prescribed for treating or preventing cardiac rejection, for example, these conditions according to generally accepted medical practice, such as cyclosporine (Neoral, Sandimmune), prednisone (Novo Prednisone, Apo Prednisone), azathioprine (Imuran), tacrolimus or FK506 (Prograf), mycophenolate mofetil (CellCept), OKT3 (Muromorab CO3, Orthoclone), ATGAM (equine polyclonal antibodies against human thymocytes) and thymoglobulin.
  • the compounds of this invention can be utilized in vivo, ordinarily in mammals, such as humans.
  • RNA from biopsy specimens is isolated using TrizolTM
  • RNA is reverse transcribed using an HPLC purified oligo-dT primer with T7 sequence attached.
  • the RNA and the primer is incubated at 70°C for 10 min. and put on ice.
  • First strand cDNA buffer, DTT (10 mM final cone), and dNTP mix is added and incubated for 2 min. at 37°C.
  • Reverse transcriptase is added at 500 units per reaction to a total volume of 20 ml.
  • the first strand reaction mix is incubated at 37°C for 1 hour and put on ice.
  • second strand reaction buffer 200 mM each) DNA ligase (10 units) DNA Polymerase (40 units), and RNase H (2 units) are added (all final concentrations). The volume is adjusted to 150 ml with DEPC-treated water. The second strand reaction mix is incubated at 16°C for 2 hours. 10 units of T4 polymerase are be added for an addition 5 min. of incubation (16°C) to fill in overhangs. The reaction is stopped with 10 ml of 0.5M EDTA and stored at -20°C. Double-stranded cDNA is cleaned up by phenol/chloroform extraction using phase lock gel to allow a more complete recovery of the sample. Nucleic acids are precipitated with ethanol. After second strand synthesis, an in vitro transcription and biotin-labeling of cRNA target are performed using the ENZO BioArray High Yield RNA
  • cRNA Transcript Labeling Kit (ENZO Biochem, Inc., New York, NY) according to the manufacturers protocol.
  • the labeled cRNA product is purified using RNeasy spin columns from QIAGEN according to the manufacturers protocol and ethanol-precipitated.
  • cRNA yield is quantified by spectrophotometric analysis at 260 nm and 280 nm and run on an agarose gel to detennine the size distribution of the labeled transcripts.
  • the cRNA is fragmented to sizes of approximately 100 basepairs in length prior to the hybridization to DNA microarrays. Fragmentation is performed by heating the cRNA for 10 to 45 min.
  • fragmentation buffer 40 mM Tris-acetate, pH 8.1, 100 mM KOAc, 30 mM MgOAc
  • Fragmented cRNA Test hybridization is performed using a GeneChip® Hybridization Oven (Affymetrix) on a Test 1 or a Test 2 probe array to ensure the quality of the target prior to exposing it to the GeneChip® DNA microarray.
  • the GeneChip® DNA rnicroarrays are stained with a streptavid ⁇ n-conjugate (Molecular Probes). Hybridization signals are detected using an HP GeneArray Scanner.
  • BLyS mRNA upregulation may be further verified and quantified by qRT-PCR analysis using an ABI PRISM 7700 Sequence Detection System. The relative quantitation of gene expression was analyzed, using 18S rRNA as endogenous control. One micro gram of total RNA was reverse transcribed using random hexamers and the TaqMan Reverse Transcription Reagents Kit (Perkin Elmer) following the manufacturer's protocols. The reverse transcription was carried out at 48°C for 30 min. The cDNA was then amplified using TaqMan PCR master mix containing AmpEraseUNG, dNTP, AmpliTaq Gold, primers, and SYBR dye according to the manufacturer's protocols under the universal cycling conditions of 2 min.
  • BLyS gene expression did not change significantly in left ventricular tissue samples from patients undergoing left ventricular assist device (LVAD) implantation to support function of patients' diseased native (natural) hearts. This observation shows the specificity of BLyS up regulation in allograft, tissue-specific rejection since implantation of artificial devices, such as the LVAD, can readily induce host immune responses. Immune responses to the implantation of an artificial device are distinct in that up regulation of immunoglobulin-specific genes are observed in the absence of any change in BLyS expression.
  • LVAD left ventricular assist device

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Abstract

L'invention concerne des méthodes permettant de diagnostiquer et de détecter le rejet d'une greffe cardiaque chez les patients transplantés. On a constaté que les taux élevés de BLyS sont étroitement associés au rejet de la greffe chez les patients ayant subi une transplantation cardiaque. L'invention concerne également des méthodes et des compositions permettant de bloquer l'expression et/ou l'activité de BlyS, et qui inhibent ou empêchent le rejet du tissu greffé chez les patients ayant subi une transplantation cardiaque.
PCT/US2002/019971 2001-06-26 2002-06-26 Diagnostic et traitement des rejets de tissu cardiaque WO2003001877A2 (fr)

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Application Number Priority Date Filing Date Title
AU2002322301A AU2002322301A1 (en) 2001-06-26 2002-06-26 Methods for the diagnosis and treatment of cardiac tissue rejection

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US30061701P 2001-06-26 2001-06-26
US60/300,617 2001-06-26

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7241688B2 (en) 2002-02-14 2007-07-10 3M Innovative Properties Company Aperture masks for circuit fabrication
WO2008109356A1 (fr) * 2007-03-02 2008-09-12 Mdrna, Inc. Composés d'acide nucléique permettant d'inhiber l'expression de gène tnfsf13b et utilisations de ceux-ci
WO2008119042A2 (fr) 2007-03-27 2008-10-02 Zymogenetics, Inc. Combinaison d'inhibition de blys et/ou d'inhibition d'april et immunosuppresseurs destinés au traitement de maladies autoimmunes
CN102298054A (zh) * 2011-05-27 2011-12-28 湘潭陆峰生物科技有限公司 一种猪抗人t细胞酶联免疫检测试剂盒及其检测方法
US20120264142A1 (en) * 2009-10-29 2012-10-18 Wisconsin Alumni Research Foundation Detection of b-cell activating factor as a biomarker for antibody mediated rejection in transplant recipients
US9545086B2 (en) 1999-01-25 2017-01-17 Biogen Ma Inc. BAFF, inhibitors thereof and their use in the modulation of B-cell response and treatment of autoimmune disorders
CN107586339A (zh) * 2016-07-06 2018-01-16 上海开拓者生物医药有限公司 一种BLyS抗体及其制备方法和应用

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US5989912A (en) * 1996-11-21 1999-11-23 Oligos Etc. Inc. Three component chimeric antisense oligonucleotides
WO2001075164A2 (fr) * 2000-03-30 2001-10-11 Whitehead Institute For Biomedical Research Mediateurs d'interference arn specifiques de sequences arn

Patent Citations (2)

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US5989912A (en) * 1996-11-21 1999-11-23 Oligos Etc. Inc. Three component chimeric antisense oligonucleotides
WO2001075164A2 (fr) * 2000-03-30 2001-10-11 Whitehead Institute For Biomedical Research Mediateurs d'interference arn specifiques de sequences arn

Non-Patent Citations (3)

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Title
MOORE ET AL.: 'BLys: member of the tumor necrosis factor family and B lymphocyte stimulator' SCIENCE vol. 28, July 1999, pages 260 - 263, XP002142252 *
SCHNEIDER ET AL.: 'BAFF a novel ligand of the tumor necrosis factor family, stimulates B cell growth' J. EXP. MED. vol. 189, no. 11, 07 June 1999, pages 1747 - 1756, XP000915409 *
ZHANG ET AL.: 'Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus' JOURNAL OF IMMUNOLOGY vol. 166, January 2001, pages 6 - 10, XP002960695 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9545086B2 (en) 1999-01-25 2017-01-17 Biogen Ma Inc. BAFF, inhibitors thereof and their use in the modulation of B-cell response and treatment of autoimmune disorders
US7241688B2 (en) 2002-02-14 2007-07-10 3M Innovative Properties Company Aperture masks for circuit fabrication
WO2008109356A1 (fr) * 2007-03-02 2008-09-12 Mdrna, Inc. Composés d'acide nucléique permettant d'inhiber l'expression de gène tnfsf13b et utilisations de ceux-ci
US8852591B2 (en) 2007-03-27 2014-10-07 Zymogenetics, Inc. Combination of BLyS and/or APRIL inhibition and immunosuppressants for treatment of autoimmune disease
JP2010522767A (ja) * 2007-03-27 2010-07-08 ザイモジェネティクス，インコーポレイティド 自己免疫疾患の治療のためのＢＬｙＳ阻害および／またはＡＰＲＩＬ阻害ならびに免疫抑制剤の組み合わせ
AU2008230777B2 (en) * 2007-03-27 2014-02-27 Ares Trading S.A. Combination of BLyS and/or APRIL inhibition and immunosuppressants for treatment of autoimmune disease
AU2008230777A8 (en) * 2007-03-27 2014-07-03 Ares Trading S.A. Combination of BLyS and/or APRIL inhibition and immunosuppressants for treatment of autoimmune disease
WO2008119042A3 (fr) * 2007-03-27 2009-04-30 Zymogenetics Inc Combinaison d'inhibition de blys et/ou d'inhibition d'april et immunosuppresseurs destinés au traitement de maladies autoimmunes
WO2008119042A2 (fr) 2007-03-27 2008-10-02 Zymogenetics, Inc. Combinaison d'inhibition de blys et/ou d'inhibition d'april et immunosuppresseurs destinés au traitement de maladies autoimmunes
EA030313B1 (ru) * 2007-03-27 2018-07-31 Займодженетикс, Инк. СПОСОБ СНИЖЕНИЯ УРОВНЕЙ IgM, IgG И IgA У МЛЕКОПИТАЮЩИХ И КОМПОЗИЦИЯ ДЛЯ ОСУЩЕСТВЛЕНИЯ ЭТОГО СПОСОБА
US20120264142A1 (en) * 2009-10-29 2012-10-18 Wisconsin Alumni Research Foundation Detection of b-cell activating factor as a biomarker for antibody mediated rejection in transplant recipients
US9176147B2 (en) * 2009-10-29 2015-11-03 Wisconsin Alumni Research Foundation Detection of B-cell activating factor as a biomarker for antibody mediated rejection in transplant recipients
CN102298054A (zh) * 2011-05-27 2011-12-28 湘潭陆峰生物科技有限公司 一种猪抗人t细胞酶联免疫检测试剂盒及其检测方法
CN107586339A (zh) * 2016-07-06 2018-01-16 上海开拓者生物医药有限公司 一种BLyS抗体及其制备方法和应用

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