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WO2002066052A1 - Utilisation d'un conjugue de il-6 et d'un recepteur d'il-6 pour la therapie anti-tumorale - Google Patents

Utilisation d'un conjugue de il-6 et d'un recepteur d'il-6 pour la therapie anti-tumorale Download PDF

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Publication number
WO2002066052A1
WO2002066052A1 PCT/DE2002/000533 DE0200533W WO02066052A1 WO 2002066052 A1 WO2002066052 A1 WO 2002066052A1 DE 0200533 W DE0200533 W DE 0200533W WO 02066052 A1 WO02066052 A1 WO 02066052A1
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cells
mice
conjugate
transfected
receptor
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German (de)
English (en)
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Stefan Rose-John
Andrzej Mackiewicz
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/204—IL-6
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/642—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/66—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 a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of a conjugate of IL-6 and an I -6 receptor, preferably Hyper-IL-6, for the treatment of a tumor.
  • the tumor is preferably melanoma, kidney or pancreatic carcinoma.
  • cytokine genes by appropriately transfected tumor cells has so far been tried as a strategy for increasing the immune responses to various types of cancer.
  • cytokines e.g. Tumor cells expressing TNF- ⁇ , IFN-gamma, I -2, IL-4, IL-6, IL-12, IL-18, or GM-CSF could be shown to promote or not to promote the formation of tumor-specific T lymphocytes.
  • T cell-mediated mechanisms of tumor cell killing can induce, for example Granulocyte inflammatory reactions.
  • genetically modified tumor vaccines (GMTV) based on these cytokines are in clinical investigation as specific immunotherapeutics for cancer treatment.
  • Allogeneic or autologous tumor cells were modified with the corresponding cytokine genes in order to be able to reach high concentrations of the cytokines acting as adjuvants at the vaccination site and to keep the systemic concentration low.
  • the results achieved with this approach so far do not allow a definitive conclusion to be drawn as to whether they can actually represent a sufficiently effective therapeutic approach to cancer treatment.
  • the technical problem underlying the present invention is therefore to provide a specific immunotherapeutic agent, that allows effective cancer therapy.
  • the corresponding secreted p84 glycoprotein could be detected in the supernatant of transfected cells and showed full activity on BAF / gpl30 cells which respond to IL-6 / sIL-6R but not to IL-6 alone.
  • the administration of recombinant H-IL-6 to C57BL / 6 mice led to a prolonged expression of an acute phase protein, which indicates a long systemic residence time of the fusion protein.
  • Transfected Bl ⁇ cells (B16 / H-IL-6 cells) showed morphological changes together with a dramatic growth inhibition in vitro.
  • mice The subcutaneous injection into C57BL / 6 mice resulted in a virtually complete rejection of the B16 / H-IL-6 cells, this effect being partially reversed in mice transgenic for a GM-CSF receptor antagonist. This indicates a GM-CSF-dependent rejection of cells transfected with H-IL-6.
  • APC antigen presenting cells
  • the present invention thus relates to the use of a conjugate of IL-6 and an 11-6 receptor or a DNA sequence encoding this conjugate for the treatment of a tumor.
  • conjugate of IL-6 and an IL-6 receptor refers to a polypeptide, the IL-6 (or the biologically active part of IL-6) and the IL-6 receptor (or for the ligand Binding responsible part of the receptor).
  • This polypeptide can be a polypeptide in which, for example, the two partners are linked to one another via covalent or non-covalent bonds in accordance with routine methods known to the person skilled in the art.
  • the two polypeptides can, for example, be linked to one another via a disulfide bridge.
  • the conjugate is preferably a fusion protein composed of IL-6 and an IL-6 receptor.
  • the conjugate preferably contains the soluble part of the IL-6 receptor (sIL-6R), ie the extracellular or soluble subunit of the interleukin-6 receptor.
  • sIL-6R soluble part of the IL-6 receptor
  • the two polypeptides of the fusion protein are linked via a peptide linker.
  • the conjugate is an IL-6 / SIL-6R fusion protein
  • Hyper-IL-6 i.e. a fusion polypeptide that contains a human sIL
  • IL-6 / sIL-6R fusion protein used in the present application includes the fusion protein with the amino acid sequence shown in DE 196 08 813 C2, as well as a fusion protein which is different from that in DE 196 08 813 C2 disclosed fusion protein in that it has deletions, additions or substitutions of one or more amino acids and / or (a) modified amino acid (s), wherein the biological activity is not significantly affected. Whether such a fusion protein still has the desired biological properties can be investigated using customary methods, for example using the method described in the examples below become .
  • the conjugate preferably Hyper-IL-6
  • an immunotherapeutic agent i.e. in the form of allogeneic or autologous tumor cells which are transformed with a DNA sequence which encodes the polypeptide, preferably Hyper-IL-6, and which is expressed.
  • suitable transformation systems and vectors e.g. for gene therapy, and in this connection reference is made to DE 196 08 813 C2 and the examples below.
  • the e.g. Hyper-IL-6 coding DNA sequence inserted into a vector suitable for gene therapy e.g. a vector based on a virus, for example an adenovirus, vaccinia virus or an AAV virus.
  • Retroviruses are particularly preferred. Examples of suitable retroviruses are MoMuLV, HaMuSV, MuMTV, RSV or GaLV. Other suitable viruses are fowlpox virus, canarypox virus, influenza virus or Sindbis virus as the basis of a vaccine.
  • the DNA sequence encoding Hyper-IL-6 can also be transported to the target cells in the form of colloidal dispersions. These include, for example, liposomes or lipoplexes (Mannino et al., Biotechniques 6 (1988), 682).
  • An allogeneic melanoma cell line (eg Mich-1 or Mich-2) is transduced with eg Hyper-IL-6 cDNA, preferably MSCV-based dicistronic retroviral double copy vectors being used. Two proteins are read from a transcript, this being achieved by using an "internal ribosome entry" site. After expansion, the grown cells are trypsinized, irradiated (for example with 100 Gy using Co-60 or 6 MV photons), aliquoted and frozen in liquid nitrogen. Before the
  • the cells are frozen with regard to contamination
  • Vaccination thawed The vaccination of the patients can be done subcutaneously (for example with 5 x 10 7 cells), with the patients initially being immunized four times at intervals of two weeks, then once a month for a year and then at intervals of two months. If the disease progresses, vaccination can take place more often, for example eight times in the beginning
  • conjugate defined above for the treatment of melanoma, kidney or pancreatic carcinoma.
  • the immune response against B16 cells induced by H-IL-6 depends on the presence of GM-CSF, it can be advantageous for the use according to the invention not only the IL- 6 / IL-6R conjugate but also to administer GM-CSF (eg as a substance or via transfection of the cells with a DNA sequence encoding GM-CSF).
  • GM-CSF eg as a substance or via transfection of the cells with a DNA sequence encoding GM-CSF.
  • the present invention thus also relates to the use of a conjugate of IL-6 and an 11-6 receptor in combination with GM-CSF.
  • the fusion protein cDNA contains a 39 bp stretch encoding a flexible linker between SIL-6R and IL-6.
  • H-IL-6 10 7 Bl6 / H-IL-6 cells were incubated for 24 hours in 5 ml of medium containing 0.1 FCS. 100 ul supernatant was used for the Western blot analysis with an anti-IL-6 antibody. H-IL-6 could only be detected as a protein with a relative molecular mass of 84 kD in the supernatant of transfected B16 cells. The right lanes were loaded with 200 ng recombinant IL-6 or SIL-6R.
  • Figure 2 Biological activity of Hyper-IL-6 (a) proliferation of BAF / gpl30 cells in response to increasing amounts of H-IL-6 and IL-6
  • Figure 3 Growth inhibition and morphological changes of H-IL-6 transfected Bl6 melanoma cells
  • Bl6 / H-IL-6 cells show an elongated morphology and tend to form cell protrusions.
  • FIG. 4 MHC-1 expression in unchanged Bl6 / H-IL-6 cells.
  • the surface expression of MHC-1 molecules K b and D ° B16 / H-IL-6 cells and control cells were determined by FACS using an anti-H-2K b D b -MAK.
  • FIG. 5 Tumor growth in mice to which H-IL-6 transfected, sham-transfected or parental Bl6 melanoma cells s.c. had been injected
  • Figure 6 Reduced growth inhibition of Bl6 / H-IL-6 cells in mice transgenic for a GM-CSFR antagonist
  • 5 ⁇ 10 5 parental Bl6 cells were injected into transgenic mice and wild-type mice.
  • the H-IL-6 cDNA was prepared using the vectors pCDM8-sIL-6R and pCDM8-IL-6, of which the sIL-6R and IL-6 cDNAs were generated by PCR.
  • the linker cDNA was introduced using Xhol sites at the C-terminus of SIL-6R and at the N-terminus of IL-6.
  • H-IL-6 cDNA was re-inserted into the vector pCDM8 using an N-terminal Mot1 and a C- terminal Hindlll site ligated.
  • the cell line B16 / H-IL-6 was transfected with 20 ⁇ g pCDM8-H-IL-6 DNA together with 2 ⁇ g pSV2Neo plasmid DNA (Southern and Berg, J.Mol .Appl .Genet. 1 (1982) , 327-341) (coprecipitation with calcium phosphate).
  • C Cell Culture and Assavs The cells were grown in DMEM at 5% CO 2 in a water-saturated atmosphere. All cell culture media were supplemented with 10% FCS, 100 mg / ml streptomycin and 60 mg / 1 penicillin. The proliferation of B16 and B16 / H-IL-6 cells was shown in
  • the density of the living cells was determined after 24, 48, 72, 96 and 120 hours using the MTT (3 - [4, 5 - dimethyththiazol - 2 - yl] - 2, 5 - diphenyltetrazolium bromide) assays the mitochrondrial
  • mice were used for the tumor-inducing experiments and FI crossings from mice transgenic for the FVB / N GM-CSF receptor antagonist and C57BL / 6 mice. The experiments were carried out with the tg2 strain.
  • flow cytometry analyzes were carried out using a "FACScan” device (Becton Dickinson, Mountain View, CA, USA). Debris and dead cells were separated and living cells were plotted using the "FACScan Lysis II" software (Becton Dickinson). As a control, the same experiment was carried out with an antibody specific for IgG2.
  • Bl6 cells were grown with a plasmid containing the cDNA for the fusion protein H-IL-6 under the control of the CMV promoter
  • Neo-resistant clones were evaluated for the expression of the H-
  • Il-6 protein screened by testing the activity of cell supernatants from BAF3 / gpl30 cells. For this example, two positive clones were selected and one sham-transfected clone that contained only the pSV2-neo plasmid.
  • Figure lb shows the expression of the 84 kD glycoprotein of a positive transfectant, detected by immunoprecipitation of the radioactively labeled protein from the supernatant via an anti-IL-6 antibody. Negative transfectants and parental Bl6 cells did not secrete H-IL-6 into the medium.
  • Figure lc shows a Western blot analysis of the medium of transfected and parental B16 cells after a tenfold concentration.
  • the IL-6 / sIL-6R fusion protein was detected with the anti-IL-6 antibody as efficiently as recombinant IL-6. There was no cross-reaction of the anti-IL-6 MAK with SIL6R (right lane).
  • the H-IL-6 levels in the supernatant of transfected cells were determined by measuring the biological Activity of the fusion protein determined on a BAF3 cell line (BAF3 / gpl30) transfected with gpl30 (FIG. 2b). Untransfected BAF3 cells did not express gpl30 and IL-6R and therefore do not respond to IL-6 or H-IL-6.
  • FIG. 2b Cell supernatants from transfected B16 cells were harvested after 24 hours and a dose-dependent proliferation of the BAF3 / gpl30 cells was observed.
  • the EC 50 concentration was determined to be 0.2 ⁇ l / ml (FIG. 2b). This corresponds to H-IL-6 levels of 500 pg / ml / 10 7 cells / 24 hours (FIG. 2a).
  • the biological activity of H-IL-6 in vivo and its stability were tested by injection (ip) of 2 ⁇ g recombinant H-IL-6 in C57BL / 6 mice.
  • the expression of the acute phase protein haptoglobin was analyzed after 72 hours by determining the serum level by means of Western blot analyzes (FIG. 2c).
  • H-IL-6 can induce acute phase proteins in mice at much lower doses than IL-6.
  • Figure 3a shows the proliferation of parental B16 and transfected Bl6 / H-IL-6 cells, which was measured over a period of five days at different times. Cell growth was significantly inhibited in Bl6 / H-IL-6 cells and cell densities were approximately 10% compared to the parental B16 cells at the end of the time series.
  • transfected Bl6 cells showed an altered morphology, which was caused by prolonged cell bulges, loss of Pigmentation and a contiguity in long rows was marked, which indicates a differentiation status (Figure 3b).
  • mice which had received parental B16 cells were injected ip three times a week with 3 ⁇ g recombinant H-IL-6 , After two weeks, the mice were sacrificed and the tumor weights were determined. This systemic Treatment with recombinant H-IL-6 reduced tumor growth by about 40 to 50%.
  • GM-CSF has been thought to play a key role in the rejection of tumor cells by the immune system.
  • transfected and parental Bl6 cells were injected into mice transgenic for the mutated K14E / E21K GM-CSF protein.
  • This GM-CSF mutein has recently been shown to bind to the GM-CSF receptor ⁇ chain, but not to stimulate the signal-transducing ⁇ unit of the GM-CSF receptor complex.
  • the K14E / E21K-GM-CSF protein behaves as a GM-CSF receptor antagonist.
  • mice transgenic for the K14E / E21K-GM-CSF antagonist showed levels of 2 to 15 ng / ml in the serum (FIG. 6a).
  • Transgenic and non-transgenic control mice were sacrificed after two weeks and the tumor volumes were determined as described above.
  • the tumor growth of the Bl6 / H-IL-6 cells in wild-type mice FVB / N x C57BL / 6 was comparable to that in C57BL / 6 mice with an average tumor volume of 50 to 100 mm 3 .
  • transgenic GM-CSF Kl4E / E21K mice were an order of magnitude higher than in the non-transgenic control mice (900 mm 3 ), which indicates that the rejection of the transfected tumor cells was dependent on the presence of biologically active GM-CSF ( Figure 6b).
  • Tumors produced by parental B16 cells in both transgenic and wild-type mice were comparable to those in C57BL / 6 mice.

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Abstract

La présente invention concerne l'utilisation d'un conjugué de IL-6 et d'un récepteur d'IL-6, de préférence Hyper-IL-6, pour traiter une tumeur. Les tumeurs traitées sont de préférence le mélanome, et le carcinome du rein ou du pancréas.
PCT/DE2002/000533 2001-02-16 2002-02-14 Utilisation d'un conjugue de il-6 et d'un recepteur d'il-6 pour la therapie anti-tumorale Ceased WO2002066052A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10107737.8 2001-02-16
DE10107737A DE10107737A1 (de) 2001-02-16 2001-02-16 Verwendung eines Konjugats aus IL-6 und einem IL-6 Rezeptor zur Tumortherapie

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010081738A1 (fr) * 2009-01-16 2010-07-22 Agirx Limited Compositions vaccinales
EP2992898A1 (fr) * 2014-09-04 2016-03-09 Klinikum rechts der Isar der Technischen Universität München Adjuvant pour lymphocyte T utiles pour la vaccination thérapeutique ou prophylactique

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0413908A2 (fr) * 1989-06-01 1991-02-27 Yeda Research And Development Company Limited Fragment extracellulaire soluble du recepteur IFN-bêta 2/IL-6 humain, sa préparation et composition pharmaceutique le contenant
EP0538810A2 (fr) * 1991-10-20 1993-04-28 Yeda Research And Development Co. Ltd. Compositions pharmaceutiques contenant l'interleukine-6
WO1996036354A2 (fr) * 1995-05-15 1996-11-21 Akademia Medyczna im. K.Marcinkowskiego Vaccin anticancereux contenant des cellules transfectees avec il6/recepteur d'il6
WO1997032891A2 (fr) * 1996-03-07 1997-09-12 Angewandte Gentechnologie Systeme Gmbh Conjugue pour influer sur les interactions entre des proteines
WO1999002552A2 (fr) * 1997-07-10 1999-01-21 Yeda Research And Development Co. Ltd. Proteine chimere du recepteur d'interleukine-6 soluble/ligand, analogues de celle-ci et applications
WO2000078331A2 (fr) * 1999-06-21 2000-12-28 Yeda Research And Development Co. Ltd. Chimere il6ril6 destinee au traitement des maladies neurodegeneratives

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0413908A2 (fr) * 1989-06-01 1991-02-27 Yeda Research And Development Company Limited Fragment extracellulaire soluble du recepteur IFN-bêta 2/IL-6 humain, sa préparation et composition pharmaceutique le contenant
EP0538810A2 (fr) * 1991-10-20 1993-04-28 Yeda Research And Development Co. Ltd. Compositions pharmaceutiques contenant l'interleukine-6
WO1996036354A2 (fr) * 1995-05-15 1996-11-21 Akademia Medyczna im. K.Marcinkowskiego Vaccin anticancereux contenant des cellules transfectees avec il6/recepteur d'il6
WO1997032891A2 (fr) * 1996-03-07 1997-09-12 Angewandte Gentechnologie Systeme Gmbh Conjugue pour influer sur les interactions entre des proteines
WO1999002552A2 (fr) * 1997-07-10 1999-01-21 Yeda Research And Development Co. Ltd. Proteine chimere du recepteur d'interleukine-6 soluble/ligand, analogues de celle-ci et applications
WO2000078331A2 (fr) * 1999-06-21 2000-12-28 Yeda Research And Development Co. Ltd. Chimere il6ril6 destinee au traitement des maladies neurodegeneratives

Non-Patent Citations (2)

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Title
MACKIEWICZ A ET AL: "Interleukin-6-type Cytokines and their receptors for gene therapy of melanoma", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, NEW YORK ACADEMY OF SCIENCES, NEW YORK, NY, US, vol. 762, 1995, pages 361 - 374, XP002087945, ISSN: 0077-8923 *
SCHAEFER KARL-HERBERT ET AL: "The IL-6/sIL-6R fusion protein hyper-IL-6 promotes neurite outgrowth and neuron survival in cultured enteric neurons", JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, MARY ANN LIEBERT, NEW YORK, NY, US, vol. 19, no. 5, May 1999 (1999-05-01), pages 527 - 532, XP002169391, ISSN: 1079-9907 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010081738A1 (fr) * 2009-01-16 2010-07-22 Agirx Limited Compositions vaccinales
EP2992898A1 (fr) * 2014-09-04 2016-03-09 Klinikum rechts der Isar der Technischen Universität München Adjuvant pour lymphocyte T utiles pour la vaccination thérapeutique ou prophylactique

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