WO1989000168A1 - Nouveau recepteur d'interleukine 2 et ses applications - Google Patents

Nouveau recepteur d'interleukine 2 et ses applications Download PDF

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Publication number
WO1989000168A1
WO1989000168A1 PCT/US1988/001806 US8801806W WO8900168A1 WO 1989000168 A1 WO1989000168 A1 WO 1989000168A1 US 8801806 W US8801806 W US 8801806W WO 8900168 A1 WO8900168 A1 WO 8900168A1
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WO
WIPO (PCT)
Prior art keywords
cells
lak
receptor
antibody
lymphokine
Prior art date
Application number
PCT/US1988/001806
Other languages
English (en)
Inventor
Thomas A. Waldmann
Warren J. Leonard
Original Assignee
The United States Of America, As Represented By Th
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 The United States Of America, As Represented By Th filed Critical The United States Of America, As Represented By Th
Publication of WO1989000168A1 publication Critical patent/WO1989000168A1/fr

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Classifications

    • 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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • 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
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
    • 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 is related to the field of receptor molecules and complexes. More particularly, the present invention is related to a new polypeptide receptor for interleukin-2 (IL-2) having a molecular weight of about 70-75,000, which is also a component of the high affinity IL-2 receptor. The invention further relates to antibodies against this new polypeptide and recombinant interleukins which have binding affinity for the new receptor.
  • IL-2 interleukin-2
  • the first category includes those types of cells which must express high affinity IL-2 receptors and express the Tac antigen (defined by anti-Tac monoclonal antibody, denoted herein as p55) for interaction with IL-2 and are designated herein as "Tac-positive" cells.
  • An example of a Tac-positive cell is the activated T cell.
  • the second category includes those types of cells which do not express high affinity IL-2 receptors or p55, but interact with IL-2 by expressing a novel glycoprotein, designated herein as "p70-75", which is distinct and different from p55.
  • p55 negative p70-75 expressing cells are resting large granular lymphocytes (LGL), natural killer (NK) and precursors of lymphokine-activated-killer (LAK) cells.
  • LGL lymphocytes
  • NK natural killer
  • LAK lymphokine-activated-killer
  • an object of the present invention to provide a new p70-75 peptide having binding affinity, for IL-2 at an epitopic site different from that of the p55. It is a further object of the present invention to provide antibodies having specific binding affinity for p70-75. It is another object of the present invention to provide an altered IL-2 molecule, designated "IL-2W 1 ", having epitopes required for binding with the p70-75 but devoid of epitopes required for binding with the p55.
  • IL-2W 2 altered IL-2 molecule, designated "IL-2W 2 ", having epitopes required for binding with the p55 peptide but devoid of epitopes required for binding with the p70-75 peptide. It is an additional object of the present invention to provide a method of producing LAK cells by reacting LGL cells with IL-2W 1 . It is yet another object of the present invention to provide a method of destroying LAK-susceptible cells by contacting said LAK-susceptible cells with LAK cells produced by reacting LGL cells with IL2-W 1 .
  • a still further object of the present invention is to provide a pharmaceutical composition comprising an effective amount of LAK cells, produced by reacting LGL cells with IL2-W 1 , to destroy LAK-susceptible cells; and a pharmaceutically acceptable carrier.
  • This combination may optionally further contain IL2-W 1 in an amount sufficient to maintain sustained killer activity of LAK cells.
  • Figure 1 is a schematic representation of a multichain model of IL-2 receptor in which an independently .existing p55 or p70-75 represent low and intermediate affinity receptors, respectively, whereas high affinity receptors are present when both p55 and p70-75 are associated in a receptor complex.
  • Activated T cells as shown in the center express both p55 and p70-75 and manifest high affinity receptors. Such high affinity receptors are required for certain T cell functions.
  • lymphokine activated killer precursor cells and natural killer cells express only the p70-75 peptide as shown on the left and manifest intermediate affinity receptors. Such cell types can respond to IL-2 utilizing the p70-75 IL-2 binding peptide alone.
  • a polypeptide characterized by a molecular weight of about 70-75,000 and which binds specifically to an epitope contributed to by amino acids 1-25 of interleukin 2.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned hereunder are incorporated herein by reference. Of course, apart from being distinct from the p55, the p70-75 of the present invention has the following additional properties.
  • LGL cells obtained from normal human peripheral blood express the p70-75 peptide alone, that is this cell population expresses an IL-2 receptor (P70-75), which is not recognized by anti-Tac monoclonal antibody.
  • P70-75 an IL-2 receptor
  • LGL leukemic cells manifest only p70-75 and not p55.
  • IL-2 dependent cell line such as LGL leukemia cells
  • Spleen cell suspension are obtained by teasing of the spleen and lysis of red blood ceils with standard ACK lysing buffer (155mM NH 4 CI, 10mM KHCO 3 , CClmM Na2 ⁇ EDTA and distilled water). Cell fusions are carried out according to the standard procedure of Kohler and Milstein (Nature, 256:495, 1975). 150 million spleen cells are fused with 3 x 10 7 NSl mouse myeloma cells using 30% polyethylene glycol (MW 1,000, Backers, Philipsburg, N.J.) dissolved in Delbecco's Modified Eagle's Media.
  • Cells are resuspended in medium and are distributed into flat bottom microtiter plates where they are selected by feeding with HAT media containing 0.1 mM hypoxanthine, 0.4 uM aminopterin, 16 mM thymidine. Fifteen days after cell fusion the culture supernatants from the wells are tested for antibody activity by an ELISA technique to determine reactivity aginst cell lines (e.g. MLA 144 and HUT 78) that express the p70-75 and non-reactivity against cell lines (e.g. MT-1) that do not express p55. After screening, hybridoma cultures that showed an appropriate pattern of reactivity, are expanded and cloned by a limiting dilution method.
  • HAT media containing 0.1 mM hypoxanthine, 0.4 uM aminopterin, 16 mM thymidine.
  • Blocking antibodies are defined by their ability to inhibit the binding of radioactive IL-2 to cell lines such as MLA 144 that express p70-75 but not p55.
  • Non-blocking antibodies are defined by their ability to precipitate radiolabelled IL-2 crosslinked to p70-75.
  • radiolabelled IL-2 can be easily prepared by routine standard procedures well known in the art.
  • anti-idiotype antibodies to antibodies that are directed toward IL-2 are prepared.
  • the immunogen is an antibody to the part of the IL-2 molecule that is involved in IL-2 binding to the p70-75.
  • anti-IL-2 antibodies are defined by their ability to bind to unbound IL-2 or IL-2 bound to p55 but are unreactive to IL-2 bound by crosslinking to p70-75.
  • Antibodies to the idiotype of such antibodies toward IL-2 also crossreact with the part of the p70-75 IL-2 binding receptor involved in IL-2 binding.
  • the procedure for the production of a monoclonal antibody vide supra is utilized with the exception that use is made of the monoclonal antibody directed toward IL-2 as the immunogen in lieu of the cell lines expressing p70-75.
  • cytotoxic agents for instance with ricin A or salmonella toxin or cytotoxic radionuclides and the like
  • antibodies of the present invention are useful in neutralizing or killing p70-75 expressing cells such as p70-75 expressing leukemias and those conditions (such as autoimmune disease or organ allograft protocols) which arise due to the abnormal interaction or pathophysiology caused by the expression of p70-75.
  • the p70-75 is obtained from any of the Tac-negative, IL-2 responsive cell lines, a few examples of which have been mentioned herein above.
  • Anti-p70-75 and a control monoclonal UPC10 are used to generate immunoaffinity columns. Imunoaffinity columns are prepared by coupling purified anti-p70-75 and UPC10 monoclonal antibodies to cyanogen bromide activated sepharose.
  • HUT-78 cells are grown in 10% fetal bovine serum/RPMI media collected by ultrafiltration washed twice in phosphate buffered saline and solubized in an extraction buffer containing 10mM Tris pH 7.4, 0.15 M sodium chloride 100 micrograms ml -1 phenylmethyl sulfonylfluoride (PMSF) 1% Triton-X-100. Extracts are centrifuged and the top lipid layer is discarded. The remaining supernatant is passed over a UPC10 column four times and then over an anti-p70-75 column three times.
  • PMSF phenylmethyl sulfonylfluoride
  • the anti-p70-75 column is washed with extraction buffer, then with 10mM Tris pH 7.5, 0.5M NaCl, 1% Triton-X-100, then with 10mM Tris pH 7.5, 0.2% triton-X-100 and then with 10mM of Tris pH 7.5.
  • the anti-p70-75 column is then eluted with 2.5% (v/v) acetic acid.
  • the eluted protein is lyophilized, resuspended in phosphate buffered saline and an aliquot is analyzed on SDS-polyacrylamide gels under reducing conditions: Gels are silver stained to assess the yield and purity.
  • Preparation of Altered IL-2 IL-2W 1 molecules that bind to p70-75 alone and IL-2W 2 molecules that bind to p55 alone are generated by constructing mutants by site directed mutagenesis.
  • 18 bases long oligonucleotide chains are synthesized using commercially available DNA synthesizers.
  • the oligonucleotides are complementary to the DNA of the IL-2 gene that has been cloned and is available with the exception that they contain 1-2 mismatches.
  • the slightly mismatched short DNA segments can function as primers for DNA extention when added to the circular single stranded chains of M13 phage.
  • the resulting complete double stranded DNA will be perfectly complementary except for the mismatched bases at the primer site.
  • DNA replication After entry into E. coli, DNA replication generates two types of daughter DNA strands; wild type strands and mutant strands, the latter containing changes imposed by the mismatched primer.
  • the strands can be easily distinguished by the way they bind the corresponding oligonucleotides. Wild type daughter DNAs bind more strongly to wild type oligonucleotide while the short DNA segment that primes the mutant sequences will bind best to the mutated progeny strands that are to be selected.
  • mutations are generated in the peptide region involved in binding to p55.
  • IL-2W 2 that binds to p55 but not to the ⁇ 70-75 peptide is generated using a slightly mismatched oligonucleotide that has a mismatch at the bases encoding the amino acids involved in binding to p70-75 but not at the site involved in binding to p55.
  • Activation of NK or LAK cells To activate natural killer (NK) and lymphokine activated killer (LAK) cells without activating T lymphocytes, IL-2W 1 is selectively and advantageously employed. At present lymphokine activated killer cells are generated by incubating peripheral blood mononuclear cells with natural IL-2. The activated cells are then readministered to the patient along with daily intravenous doses of IL-2.
  • IL-2W 1 which interacts only with the p70-75, is substituted in vitro and/or in vivo for natural IL-2 for the generation and maintenance of LAK cells.
  • IL-2W 1 binds to the p70-75 which is the receptor for IL-2 on large granular lymphocytes (the precursors of natural killer and lymphokine activated killer cells) and is sufficient for IL-2 activation of these cells.
  • many T cell functions depend on the simultaneous binding of IL-2 to the p55 and p70-75 IL-2 binding peptides of the high affinity receptor complex. Since IL-2W 1 does not bind to the Tac peptide, it does not activate T-cells at the concentrations used. Thus, IL-2W 1 activates the large granular lymphocytes to become effective natural killer and lymphokine activated killer cells without simultaneously activating T lymphocytes to become activated cells that synthesize toxic lymphokines.
  • lymphokine IL-2W 1 in contrast to natural IL-2, the desired lymphokine activated killer cells to destroy the tumor cell populations are activated without activating T lymphocytes and their toxic lymphokine.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
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  • Genetics & Genomics (AREA)
  • Immunology (AREA)
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  • Gastroenterology & Hepatology (AREA)
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  • Veterinary Medicine (AREA)
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Abstract

La présente invention se rapporte au domaine des molécules et complexes récepteurs, et plus précisément à un nouveau récepteur de polypeptides destinés à l'interleukine 2, dont le poids moléculaire est d'environ 70 à 75000, et qui est un constituant du récepteur de l'IL-2 à haute affinité, à des anticorps dressés contre ce nouveau polypeptide, ainsi qu'à des interleukines recombinantes capables de lier le nouveau récepteur. Sont également décrites diverses applications du récepteur p70-75, des anticorps anti p70-75 de l'IL-2W1 et de l'IL-2W2.
PCT/US1988/001806 1987-06-29 1988-05-27 Nouveau recepteur d'interleukine 2 et ses applications WO1989000168A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US6698987A 1987-06-29 1987-06-29
US066,989 1987-06-29
US16530288A 1988-03-03 1988-03-03
US165,302 1988-03-08

Publications (1)

Publication Number Publication Date
WO1989000168A1 true WO1989000168A1 (fr) 1989-01-12

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PCT/US1988/001806 WO1989000168A1 (fr) 1987-06-29 1988-05-27 Nouveau recepteur d'interleukine 2 et ses applications

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AU (1) AU1992388A (fr)
CA (1) CA1340437C (fr)
IL (1) IL86710A0 (fr)
WO (1) WO1989000168A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0386289A1 (fr) * 1989-03-07 1990-09-12 Taniguchi, Tadatsugu, Dr. Récepteur d'interleukine-2 recombinant
EP0395853A1 (fr) * 1989-03-07 1990-11-07 BOEHRINGER INGELHEIM INTERNATIONAL GmbH Récepteur d'interleukine-2 recombinant
EP0408790A1 (fr) * 1989-07-20 1991-01-23 Taniguchi, Tadatsugu, Dr. Récepteur protéique recombinant
US5449756A (en) * 1989-03-07 1995-09-12 Boehringer Ingelheim International Gmbh Recombinant protein receptor for IL-2
US5679160A (en) * 1995-06-07 1997-10-21 Nd Industries, Inc. Apparatus for coating threaded fasteners
US5807743A (en) * 1996-12-03 1998-09-15 Ribozyme Pharmaceuticals, Inc. Interleukin-2 receptor gamma-chain ribozymes

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACT., Vol. 107, issued 1987, "The Signal Transduction at IL-2 Receptor", Abst. No. 234538m, (SUGIE), JIKKEN IGAKU, 5(9), pages 811-15. *
CHEMICAL ABSTRACT., Vol. 108, issued 1987, "Structure/Function Analysis of IL-2 Binding Proteins on Human B-cell Precursor Acute Lymphoblastic Leukemia", Abst. No. 20277x, (WORMANN), Leukemia, 1(9), pages 660-66. *
EUR. J. IMMUNOL., Vol. 14, issued April 1984, "Partial Characterization of the Putative Rat IL-2 Receptor", (OSAWA), pages 374-6, see page 374. *
IMMUNOBIOLOGY, Vol. 175, issued 1987, "The Mouse High Affinity IL-2 Receptor Complex", (HERRMAN), pages 145-158, BIOSIS ABSTRACT NO. 88:50575. *
J. EXP. MED., Vol. 161, issued May 1985, "TLiSA1, Human Lineage-Specific Activation Antigen Involved in the Differentiation of Cytotoxic T-Lymphocytes and Anamalous Killer Cells from their Precursor", (BURNS), pages 1063-78, see page 1063. *
J. EXP. MED., Vol. 165, issued April 1987, "Internatilization of IL-2 is Mediated by the Beta Chain of the High-affinity IL-2 Receptor", (ROBB), pages 1201-6, see page 1201. *
J. IMMUNOL., Vol. 135, issued July 1985, "IL-2 Receptor Induction on Human T-Lymphocytes", (WAKASUGI), pages 321-27, see page 321. *
J. IMMUNOL., Vol. 139, issued December 1987, "Binding of IL-2 to it's 75 kDa Intermediate Affinity Receptor is Sufficient to Activate Sodium/Proton Exchange", (MILLS), pages 4083-87, see page 4083. *
J. IMMUNOL., Vol. 139, issued September 1987, "IL-2 Activates a Receptor-Associated Protein Kinase", (BENEDICT), pages 1694-97, see page 1694. *
J. IMMUNOL., Vol. 139, issued September 1987, "The Murine IL-2 Receptor", (SARAGOVI), pages 1918-26, see page 1918. *
NATURE, Vol. 327, issued June 1987, "A Second Human IL-2 Binding Protein that may be a Component of High Affinity IL-2 Receptor", (DUKOVICH), pages 518-22, see page 518. *
PROC. NATL. ACAD. SCI., Vol. 83, issued December 1986, "Demonstration of a Non-Tac Peptide that Binds IL-2", (TSUDO), pages 9694-98, see page 9694. *
SAPPORO MED. J., Vol. 55, issued 1986, "Construction of Rat-Mouse T-Cell Hybridomas that Express the Rat IL-2 Receptor and analysis of Mechanisms involved in the Regulation of their Expression", (KOHDA), pages 453-73, BIOSIS ABSTRACT NO. 87:4199. *
SCIENCE, Vol. 234, issued November 1986, "Novel IL-2 Receptor Subunit Detected by Cross-Linking under High-Affinity conditions", (SHARON), pages 859-63, see page 859. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0386289A1 (fr) * 1989-03-07 1990-09-12 Taniguchi, Tadatsugu, Dr. Récepteur d'interleukine-2 recombinant
EP0386304A1 (fr) * 1989-03-07 1990-09-12 Taniguchi, Tadatsugu, Dr. Récepteur d'interleukine-2 recombinant
EP0395853A1 (fr) * 1989-03-07 1990-11-07 BOEHRINGER INGELHEIM INTERNATIONAL GmbH Récepteur d'interleukine-2 recombinant
US5198359A (en) * 1989-03-07 1993-03-30 Boehringer Ingelheim International Gmbh Recombinant protein receptor for il-2
US5449756A (en) * 1989-03-07 1995-09-12 Boehringer Ingelheim International Gmbh Recombinant protein receptor for IL-2
EP0408790A1 (fr) * 1989-07-20 1991-01-23 Taniguchi, Tadatsugu, Dr. Récepteur protéique recombinant
US5679160A (en) * 1995-06-07 1997-10-21 Nd Industries, Inc. Apparatus for coating threaded fasteners
US5807743A (en) * 1996-12-03 1998-09-15 Ribozyme Pharmaceuticals, Inc. Interleukin-2 receptor gamma-chain ribozymes

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Publication number Publication date
CA1340437C (fr) 1999-03-16
AU1992388A (en) 1989-01-30
IL86710A0 (en) 1988-11-30

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