EP0792294A1 - Anticorps humains pour les peptides recepteurs de lymphocytes t et leur methode de preparation - Google Patents

Anticorps humains pour les peptides recepteurs de lymphocytes t et leur methode de preparation

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Publication number
EP0792294A1
EP0792294A1 EP95939984A EP95939984A EP0792294A1 EP 0792294 A1 EP0792294 A1 EP 0792294A1 EP 95939984 A EP95939984 A EP 95939984A EP 95939984 A EP95939984 A EP 95939984A EP 0792294 A1 EP0792294 A1 EP 0792294A1
Authority
EP
European Patent Office
Prior art keywords
antibodies
human
bind
tcr
antibody
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP95939984A
Other languages
German (de)
English (en)
Inventor
William J. Landsperger
John J. Marchalonis
Douglas F. Lake
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Arizona Board of Regents of University of Arizona
Baxter International Inc
University of Arizona
Original Assignee
Arizona Board of Regents of University of Arizona
Baxter International Inc
University of Arizona
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Arizona Board of Regents of University of Arizona, Baxter International Inc, University of Arizona filed Critical Arizona Board of Regents of University of Arizona
Publication of EP0792294A1 publication Critical patent/EP0792294A1/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
    • C07K16/065—Purification, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to antibody preparations that are enriched for antibodies capable of binding to certain T-lymphocytes. More particularly, the invention relates to human antibody preparations that are enriched for antibodies which bind to human T-cell receptor variable region peptides and conformational determinants. The invention further relates to certain methods for making such antibody preparations. These antibody preparations are useful for diagnosing immune system disorders, such as autoimmune diseases and graft versus host disease ("GVHD”) . They also have potential therapeutic value in treating these diseases.
  • GVHD graft versus host disease
  • T-lymphocytes are involved in cell-mediated immunity.
  • T-cells have been implicated in various immune system disorders, such as autoimmune related syndromes, including classic autoimmune diseases and GVHD.
  • IVIG intravenous immunoglobulins
  • These diseases include non-hematologic autoimmune diseases as well as immunohematologic and other diseases with immunopathologic features.
  • Patients suffering from both chronic autoimmune disease and acute GVHD have been found to respond to IVIG treatment regimens.
  • Clinical improvements have been attributed (at least in part) to certain antibodies contained in these preparations.
  • T-cells have on their surface a T-cell receptor ("Tcr") which is responsible for the immunological specificity of the cells.
  • Tcr is associated with polypeptides which form the CD3 complex.
  • the Tcr recognizes processed antigen associated with a molecule which is a product of the major histocompatibility complex (“MHC") .
  • MHC major histocompatibility complex
  • the polypeptide chains for the antigen-binding portion of the Tcr are encoded by four different gene loci, designated a , ⁇ , ⁇ and .
  • a given T-cell will express either an a/ ⁇ or a ⁇ / ⁇ receptor.
  • the Tcr's of the great majority of peripheral T-cells are composed of polypeptide products of the a/ ⁇ gene loci.
  • the genes encoding the Tcr are similar to those which encode antibody. They consist of multiple V, D and J segments which become recombined during T-cell development to produce functional VDJ or VJ genes.
  • the genes encode the N-terminal variable (V) domains of the Tcr.
  • the human genome contains approximately 100 V ⁇ genes and between 50 and 100 V ⁇ genes.
  • Kawasaki's disease and multiple sclerosis are two examples of autoimmune diseases in which T- cells are clearly implicated.
  • MS multiple sclerosis
  • patients with acute Kawasaki's disease demonstrate significantly elevated levels of circulating T-cells bearing the products V32 and Vj88.1 genes, indicative of specific up-regulation.
  • IVIG results in significant clinical improvement and a return to near-normal levels of T-cell subsets.
  • Serum from patients suffering from MS have been found to possess elevated levels of T- cells reactive with myelin base proteins, and these T- cells tend to express products of the Tcr V ⁇ 5.2 and
  • Human Tcr peptides have been used as immunogens to produce animal antisera. Schluter, S.F. and Marchalonis, J.J., Proc. Natl. Acad. Sci. USA. 83 ;1872- 76 (1986) .
  • the present invention provides a human antibody preparation which is enriched for antibodies that bind to T cell receptor variable region peptides and conformational determinants. Also disclosed is a method of using such antibody preparation for the diagnosis or treatment of an autoimmune disease or condition or GVHD which is associated with an elevation of T-lymphocytes bearing a particular Tcr peptide or conformational determinant.
  • the invention further provides methods for making antibody preparations enriched for antibodies with binding specificities to these Tcr autoantigenic variable region epitopes.
  • the method involves combining, under antibody-antigen binding conditions, (i) a Cohn human plasma fraction which contains antibodies that bind to a human Tcr peptide sequence and (ii) a solid support to which Tcr peptide has been immobilized; separating unbound proteins from the solid support; and eluting bound antibodies from the solid support under conditions which break the antibody-antigen bonds, thereby forming an antibody preparation which is enriched for antibodies that bind to a human Tcr peptide sequence.
  • the method involves combining, under antibody-antigen binding conditions (i) a human or animal antibody mixture which contains antibodies that bind to a human Tcr peptide or conformational determinant and (ii) a solid support to which a recombinant human Tcr protein has been immobilized; separating unbound proteins from the solid support; and eluting bound antibodies from the solid support under conditions which break the antibody-antigen bonds, thereby forming an antibody preparation which is enriched for antibodies that bind to a human Tcr peptide or conformational determinant.
  • the novel antibody preparations of this invention have utility in diagnosing or monitoring the progress of human immune system disorders, such as autoimmune diseases and GVHD. These antibody preparations further have value as human therapeutic agents.
  • IVIG preparations are effective in treating immune disorders because they contain autoantibodies which bind to Tcr protein on the surfaces of T-lymphocytes.
  • the antibody preparations of the present invention provide more potent and selective therapeutic agents.
  • Figure 1 is a fluorescent activated cell sorter (FACS) scan of Jurkat cells treated with antibody free reagents (negative control) .
  • Figure 2 is a FACS scan of Jurkat cells treated with rabbit anti-scTcr antiserum (positive control) .
  • Figure 3 is a FACS scan of Jurkat cells treated with unpurified IVIG.
  • Figure 4 is a FACS scan of Jurkat cells treated with IVIG purified by immunoaffinity chromatography using immobilized scTcr.
  • Figure 5 represents ELISA results showing the reactivity of Cohn Fraction I + III with scTcr and various Tcr peptides.
  • Figure 6 represents ELISA results showing the reactivities of sera from patients with rheumatoid arthritis with scTcr.
  • Figure 7 represents ELISA results showing the reactivities of sera from patients with SLE with scTcr.
  • Figure 8 is a graph illustrating the results of cell proliferation assays comparing the inhibitory effects (shown as percent inhibition) of increasing concentrations of purified anti-03 antibodies and a commercial intravenous immunoglobulin (IVIG) .
  • Figure 9 is an overview depiction of the experimental design of an experiment to study the effects of purified antibodies in modulating T cell activity via interaction with the TcR.
  • Figure 10 is a graph illustrating the inhibition of lymphocyte killing of tumor targets by anti-TcR antibodies purified from a commercial intravenous immunoglobulin (IVIG) .
  • IVIG intravenous immunoglobulin
  • the novel antibody preparations of this invention are advantageously prepared from human antibody mixtures which contain antibodies having the desired reactivities. Healthy humans, as well as those suffering from autoimmune diseases and conditions, such as systemic lupus erythematosis and rheumatoid arthritis, and autoimmune related syndromes, such as GVHD, contain autoantibodies directed against peptide and conformational determinants occurring in Tcr proteins. See, Marchalonis et al. , Proc. Natl . Acad. Sci..
  • pooled serum from healthy individuals or those suffering from autoimmune diseases may be used as sources for the antibody preparations of this invention.
  • Commercially available plasma products or fractions also advantageously may be used as the source for these antibody preparations.
  • immune serum globulin products and commercial IVIG preparations such as Gammagard ® , available from Baxter Healthcare International, and Sandoglobulin, available from Sandoz Pharmaceuticals, can be used as a starting material .
  • Various Cohn plasma fractions (Cohn et al . , J__ Am. Chem. Soc ..
  • novel antibody preparations are conveniently obtained by immunoaffinity purification using immobilized Tcr peptides or recombinant human Tcr proteins. The latter may be preferred because of their ability to bind to antibodies through both peptide and conformational determinants.
  • Tcr peptides are immobilized by bonding them to a conventional solid support, such as agarose beads, using well known conventional methods. See, Marchalonis et al. , 1992, supra.
  • Various peptides corresponding to sequences of the Tcr antigen binding region can be used in the immunoaffinity purification procedure. These peptides are preferably encoded by Vc. and/or V ⁇ genes, but may also be encoded by V ⁇ and/or V ⁇ genes.
  • Tcr peptides chosen represent regions of the Tcr found to be autoimmunogenic as manifested by production of IgG and IgM autoantibodies. Marchalonis et al. , 1992, supra. Recombinant Tcr proteins contain these sequences. Lake et al. , Biochem. Biophys. Res. Comm.. 201 (301) : 1502- 109 (1994) .
  • Tcr peptides used for the antibody purifications may be chemically synthesized using conventional peptide synthesis techniques.
  • Recombinant human Tcr proteins may be made by various recombinant
  • DNA procedures e.g., by cDNA cloning techniques using messenger RNA obtained from commercially-available T-cell lines, or from T-cells cultured from normal blood or blood from patients suffering from autoimmune diseases.
  • Genes from the Va , V ⁇ , V ⁇ and V ⁇ loci have been sequenced (Toyonaga, B. And Mak, T.W., Ann. Rev. Immunol . , 5., 585-620 (1987) ) , and these sequences may be utilized for designing PCR primers and probes for amplifying and identifying cDNA clones.
  • particular autoimmune diseases have been associated with elevated levels of circulating T-cells bearing the products of specific Tcr genes.
  • a Tcr protein, peptide or conformational determinant is said to be associated with a particular immune system disorder or condition when T-cells bearing that determinant are elevated in patients having the disorder or condition.
  • T- cells bearing the products of the V ⁇ 2 and VS8.1 genes are said to be associated with Kawasaki's disease, because those T-cells are elevated in patients having that disease.
  • T-cells bearing the products of V/35.2 and V ⁇ 6 .1 genes are associated with MS.
  • the analysis of Tcr variable regions associated with immune system disorders is progressing at a rapid pace.
  • proteins containing those sequences can be produced by cDNA cloning procedures using published sequence information.
  • Antibody preparations enriched for antibodies which bind to a desired Tcr peptide or conformational determinant may then be prepared by the immunoaffinity procedures described herein.
  • the method of the present invention utilizes a recombinant single chain Tcr protein (scTcr) for the immunoaffinity purification of antibodies from IVIG and from Cohn Fractions I and III and from Cohn Fraction II.
  • Construction of the scTcr was based upon complete Va and V ⁇ regions of the Jurkat T-cell line.
  • the Jurkat cell line is a human monoclonal CD4", helper a/ ⁇ * leukemia T-cell line, which is available from the American Type Culture Collection, Rockville, Maryland, USA, under Accession No. ATCC 152-TIB.
  • This scTcr molecule contains the V ⁇ and V ⁇ gene products joined by a linker peptide.
  • Recombinant human Tcr proteins may also be used to prepare animal antisera enriched for antibodies which bind to human Tcr or conformational determinants.
  • the animal antisera may be prepared by immunizing animals with Tcr peptides, recombinant human Tcr proteins or human T-cells.
  • the animal antibody preparations so produced have utility as diagnostic reagents.
  • the novel purified antibodies of this invention may be of any isotype, and those purified from Cohn Fractions I and III are primarily of either IgG or IgM isotype.
  • the antibody preparations of this invention may be used for diagnosing or monitoring the progress of immune system disorders or conditions, including autoimmune diseases and GVHD.
  • the novel antibody preparations are used diagnostically by determining the extent to which they bind to T-lymphocytes obtained from human subjects.
  • Various immunochemical detection techniques may be used for detecting the interaction of the antibodies and T-lymphocytes. For example, ELISA and flow cytometry using a fluorescent activated cell sorter ("FACS”), as well as other conventional immunochemical procedures, may be used for the detection of the antibody-T-cell interactions.
  • FACS fluorescent activated cell sorter
  • the antibody preparations of this invention have potential therapeutic value. As indicated above, it is known that commercially available immune serum globulin preparations can be used for treating autoimmune diseases and GVHD. In accordance with this invention, it has been shown that these immunoglobulin 53 PC17US95/14869
  • preparations contain antibodies to Tcr peptide sequences and conformational determinants.
  • the antibody preparations of this invention are enriched for antibodies to Tcr peptide and conformational determinants up to about 1,000 times over the levels in unprocessed IVIG.
  • Dosages of IVIG used in the treatment of GVHD and autoimmune diseases range from 100 mg to 5 g of IVIG/kg body weight. Based upon in vi tro and in vivo studies (mouse model) , effective therapeutic doses of affinity purified antibodies are within the range of about 0.1 mg to about 100 mg/kg of body weight. Such doses can be administered by any suitable methods, with intravenous administration being preferred.
  • These antibody preparations are expected to have numerous advantages over currently-available IVIG preparations in the treatment of these diseases. These advantages arise from the higher potencies and greater selectivities of the antibody preparations of the present invention. Therefore, lower dosages and thus, lower protein loads on the patient can be realized.
  • This invention is further illustrated by the following examples, which are not intended to be
  • the plasma fraction was centrifuged and dialyzed and then filtered through 0.45 ⁇ m filter to remove insoluble Celite and particulates.
  • the resulting solution was subjected to immunoaffinity purification essentially as described by Marchalonis et al .. 1992 supra.
  • the immunoaffinity column was prepared as follows:
  • BL21 (DE3) E. coli cells were purchased from Novagen. PET21d plasmid which contained recombinant scTcr gene was used to transform the BL21 (DE3) E. coli so that the E. coli would produce the recombinant scTcr protein.
  • the recombinant protein (1.1 milligrams) was dissolved in 10 ml of 0.1 M sodium carbonate (pH 8.0) and incubated with 0.75 g of activated CH Sepharose-4B (Pharmacia Fine Chemicals, Piscataway, NJ, U.S.A.) at room temperature for 2 hours.
  • Sepharose was then washed with 40 ml of phosphate-buffered saline (50 m-M NaCl/150 mM sodium phosphate, pH 8.0) , treated with 40 ml of 1M ethanolamine (pH 8.0) for 1 hour to block unreacted sites, washed with 100 ml of TBS and packed into a 10 cm x 1 cm column.
  • phosphate-buffered saline 50 m-M NaCl/150 mM sodium phosphate, pH 8.0
  • 1M ethanolamine pH ethanolamine
  • Figures 1-4 Figure 1 represents the instrument output for the negative control, and shows a reactivity of 4.39% positive.
  • Figure 2 represents the positive control and shows a reactivity of 95.44% positive.
  • Figures 3 and 4 represent unpurified IVIG and immunoaffinity purified
  • the unpurified antibody mixture had a reactivity of 3.43% positive and the purified antibody preparation had a reactivity of 91.47% positive.
  • Hexadecapeptide antigens 03 , ⁇ B , and ⁇ _l corresponded to the first complementarity - determining region, the third framework region and the constant region of the YT35 (Jurkat T cell myeloma cell line) S-chain respectively.
  • Peptide antigens or the scTcr were dissolved in 0.2 M carbonate buffer, pH 9.6. These solutions (100 ⁇ g/ml) were added to wells of a microtiter plate and dried overnight at 37°C.
  • EXAMPLE IV The reactivities of antibodies in sera from four patients with rheumatoid arthritis ("RA") and eight patients with systemic lupus erythematosis (“SLE”) with scTcr were analyzed by ELISA using essentially the procedures described in Example III. The results are shown in Figures 6 and 7 respectively. Significant reactivities with the recombinant scTcr were observed in these patient's sera.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosis
  • EXAMPLE V Antibodies which bind to a human Tcr protein, peptide or conformational determinant were affinity purified as in Example I but from a commercial intravenous immunoglobulin (IVIG, Gammagard ® ) using column chromatography in which peptide ⁇ 3, corresponding to the first complementarity determining region of a human T cell line (also obtained from YT35?) ⁇ chain, was immobilized on CH-Sepharose. Following elution, the antibodies were immediately neutralized with NaOH-glycine. The antibodies then were used in inhibition of phytohaemagglutinin (PHA) stimulated T cell proliferation.
  • the T cell proliferation assay is a standard assay and was performed essentially as in Current Protocols in Immunology (Coligan, J.E. et al. ; 19940 Series Ed. Richard Coico) vol. I, Section 7.10 (John Wiley and
  • mice C57/BL mice were injected on day 0 with Balb/c mouse mammary derived EMT6 tumor cells.
  • the mice were surgically implanted with a gelatin sponge and the incisions were allowed to heal.
  • fresh EMT6 cells were injected into the gelatin sponges.
  • the sponges were removed, digested with gelatinase and the TRLs, which had infiltrated in order to reject the tumor cells, were recovered.
  • Antibodies which bind to a human Tcr protein, peptide or conformational determinant were affinity purified from IVIG (Gammagard ® ) using column chromatography with peptides immobilized on CH- Sepharose.
  • the peptides used corresponded to the CDR1 region of Balb/c mouse V ⁇ l (EQHLGHNAMY) and Vj88 (NQTNNHNNMY) Tcr chains.
  • the purification procedure was as described in Example 1. Final preparations of affinity purified antibody were extensively dialyzed against PBS.
  • Affinity-purified antibodies prepared using each peptide in separate purification steps plus the column flow through IVIG were evaluated in an in vi tro chromium release assay.
  • the chromium release assay was performed essentially as described in Akporiaye, E.T. and K. Muthulakshni, Cancer Immunol . Immunother . 29:199 (1989) with the following modifications. Fifty ⁇ l of the TRLs obtained above (1.5 X 10 5 cells per well) were added to appropriate wells of a 96 well culture plate. Next, 50 ⁇ l aliquots (30 ⁇ g of antibody per well) were added and the plates incubated for eight hours at 37°C.
  • the degree of cell lysis was determined by measuring the amount of chromium released in the supernatant using a gamma counter.
  • Figure 10 shows that anti-V / Sl and anti-V?8 independently gave 80% and 50% inhibition of T cell activity, respectively. Added together, they yielded 90% + inhibition. Column flow through as a control showed no inhibition.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
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Abstract

Préparations d'anticorps humains enrichies pour obtenir des anticorps qui se lient avec les peptides de récepteurs de lymphocytes T humains ou aux déterminants de conformation. L'invention décrit également les méthodes de préparation de ces anticorps à partir de fractions du plasma humain selon Cohn, par purification d'immunoaffinité, à l'aide de protéines de récepteur de lymphocytes T de recombinaison ou de peptides à région variable de récepteurs de lymphocytes T. La purification des anticorps de récepteurs de lymphocytes T à partir de mélanges d'anticorps humains ou animaux est effectuée suivant des procédures d'immunoaffinité qui font appel à des protéines de récepteurs de lymphocytes T humains de recombinaison. Les anticorps purifiés par immunoaffinité peuvent se fixer sur les récepteurs de lymphocytes T intacts liés à la membrane grâce à une sélection des cellules reposant sur la fluorescence et peuvent aussi inhiber la prolifération des lymphocytes T suite à une stimulation par le mithogène. Les anticorps polyclonaux humains purifiés par immunoaffinité peuvent inhiber l'activité lytique des cellules tueuses naturelles sur une ligne de lymphocyte T monoclonaux. Les préparations d'anticorps sont susceptibles d'être utilisées pour diagnostiquer, surveiller et soigner différents syndromes de maladies auto-immunes.
EP95939984A 1994-11-16 1995-11-15 Anticorps humains pour les peptides recepteurs de lymphocytes t et leur methode de preparation Ceased EP0792294A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US34115794A 1994-11-16 1994-11-16
US341157 1994-11-16
PCT/US1995/014869 WO1996015153A1 (fr) 1994-11-16 1995-11-15 Anticorps humains pour les peptides recepteurs de lymphocytes t et leur methode de preparation

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EP0792294A1 true EP0792294A1 (fr) 1997-09-03

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EP95939984A Ceased EP0792294A1 (fr) 1994-11-16 1995-11-15 Anticorps humains pour les peptides recepteurs de lymphocytes t et leur methode de preparation

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EP (1) EP0792294A1 (fr)
JP (1) JPH10509948A (fr)
AU (1) AU705010B2 (fr)
CA (1) CA2205138A1 (fr)
WO (1) WO1996015153A1 (fr)

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GB9904395D0 (en) * 1999-02-25 1999-04-21 Fluorescience Ltd Protein assay
US6972198B2 (en) 1999-02-26 2005-12-06 Cyclacel, Ltd. Methods and compositions using protein binding partners
AT410636B (de) * 2001-03-23 2003-06-25 Igeneon Krebs Immuntherapie Verfahren zur herstellung eines impfstoffes
US20050084967A1 (en) 2002-06-28 2005-04-21 Xcyte Therapies, Inc. Compositions and methods for eliminating undesired subpopulations of T cells in patients with immunological defects related to autoimmunity and organ or hematopoietic stem cell transplantation
EP1532983A1 (fr) 2003-11-18 2005-05-25 ZLB Bioplasma AG Preparation d'immunoglobulines à stabilité élevée
WO2011095543A1 (fr) 2010-02-04 2011-08-11 Csl Behring Ag Préparation d'immunoglobuline
EP2361636A1 (fr) 2010-02-26 2011-08-31 CSL Behring AG Préparation d'immunoglobuline et système de stockage pour préparation d'immunoglobuline
WO2013132347A2 (fr) * 2012-03-06 2013-09-12 Calpro As Immunodosage elisa amélioré de la calprotectine
ES2745472T3 (es) 2013-07-15 2020-03-02 The U S A As Represented By The Secretary Department Of Health And Human Services Office Of Tech Tra Receptores de células T anti-virus del papiloma humano 16 E6
JP2018526034A (ja) * 2015-09-10 2018-09-13 アフィジェン・インコーポレイテッド 腫瘍治療薬の配列決定により導かれる選択

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CA2018248A1 (fr) * 1989-06-07 1990-12-07 Clyde W. Shearman Anticorps monoclonaux contre le recepteur alpha-beta de cellules t humaines, leur production et leur utilisation
CA2063408A1 (fr) * 1990-05-03 1991-11-04 Susan Mayo Tissu lymphoide humain d'un hote immunodeprime

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See references of WO9615153A1 *

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CA2205138A1 (fr) 1996-05-23
WO1996015153A1 (fr) 1996-05-23
AU705010B2 (en) 1999-05-13
AU4161196A (en) 1996-06-06
JPH10509948A (ja) 1998-09-29

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