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WO1992010210A1 - Inhibition de l'angiogenese par il-1 - Google Patents

Inhibition de l'angiogenese par il-1 Download PDF

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Publication number
WO1992010210A1
WO1992010210A1 PCT/US1990/007220 US9007220W WO9210210A1 WO 1992010210 A1 WO1992010210 A1 WO 1992010210A1 US 9007220 W US9007220 W US 9007220W WO 9210210 A1 WO9210210 A1 WO 9210210A1
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WIPO (PCT)
Prior art keywords
bfgf
cells
tumor
growth
angiogenesis
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Application number
PCT/US1990/007220
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English (en)
Inventor
William Fitts Herblin
Mary Elisabeth Neville
Original Assignee
E.I. Du Pont De Nemours And Company
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Filing date
Publication date
Application filed by E.I. Du Pont De Nemours And Company filed Critical E.I. Du Pont De Nemours And Company
Priority to PCT/US1990/007220 priority Critical patent/WO1992010210A1/fr
Publication of WO1992010210A1 publication Critical patent/WO1992010210A1/fr

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    • 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
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • 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]
    • A61K38/2006—IL-1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum

Definitions

  • This invention relates to the use of interleukin-1 (IL-1) and particularly IL-1 ⁇ , as a means to inhibit anglogenesis and also the use of IL-1 ⁇ to treat anglogenesis-mediated diseases in a mammal.
  • IL-1 interleukin-1
  • IL-1 ⁇ interleukin-1 ⁇
  • IL-1 ⁇ and ⁇ are proteins which are primarily produced by monocytes and macrophages (Dinarello (1987) Bull Inst. Pasteur 85:267; Oppenhelm et al. (1986) Immunology Today 7:45) .
  • Other cells such as fibroblasts and endothelial cells can also produce IL-1 under certain conditions (Miossec et al. (1986) J. Immunol. 136:2486; Iribe et al. (1983) J. Exp. Med. 157:2190).
  • IL-1 has been implicated in many biological functions including fever induction, T-cell activation, granulopoiesis, increased
  • IL-1 also has been found to influence the breakdown and repair of tissue and bone by the stimulation of proteinases, collagenases and fibrinolysins.
  • IL-1 ⁇ and ⁇ bind to the same receptors expressed on many different cells (Dower et al. (1985) J. Exp. Med. 162:501;
  • Angiogenesis is the process of new capillary formation which usually involves the directional mobilization of endothelial cells, cellular proliferation, canalization and production of periendothelial stroma (Ausprunk and Folkman (1977) Microvasc. Res. 14:53). Angiogenesis may be required in pathological conditions such as the growth of solid tumors (Folkman (1986) Cancer Res. 46:467). rheumatoid arthritis (Matsubara and Ziff
  • angiogenesis has been described as the dominant pathology in the following diseases: retrolental fibroplasia, hemangiomas, angiofibromas, psoriasis (Folkman (1987) Science 235:442-47); and pulmonary capillary hemangiomatosis (Folkman (1989) NEJM 320:1211-12).
  • the inhibition of angiogenesis may be therapeutically beneficial in these and related diseases: retrolental fibroplasia, hemangiomas, angiofibromas, psoriasis (Folkman (1987) Science 235:442-47); and pulmonary capillary hemangiomatosis (Folkman (1989) NEJM 320:1211-12).
  • Angiogenesis requires factors, including proteins, produced by cells to orchestrate the process. Several of these proteins (Schroder et al. (1987) Proc. Natl. Acad. Sci. USA 84 :5277;
  • FGF fibroblast growth factor
  • FGF FGF-like growth factor
  • basic bFGF
  • aFGF acidic
  • Both forms bind to the same receptors (Olwin et al. (1986) Biochemistry 25:3488; Neufeld et al. (1987) J. Biol. Chem. 261:5631).
  • Both forms stimulate angiogenesis (Thomas et al. (1985) Proc. Natl. Acad. Sci. USA 82:6409; Abraham et al.
  • neovascularization (such as diabetic retinopathy or neovascular glaucoma) IL-1 may inhibit angiogenesis and thereby provide a therapeutic benefit in the treatment of these conditions.
  • This invention relates to the use of IL-1 and preferably IL-1 ⁇ in the treatment of anglogenesis-mediated and/or bFGF-mediated disease states in a mammal, and more particularly relates to administering to the mammal an angiogenesis-inhibiting amount of IL-1 ⁇ alone or in combination with other anti-angiogenic factors.
  • IL-1 ⁇ inhibits angiogenesis in vivo in an intradermal murine tumor model.
  • the ability of IL-1 to inhibit angiogenesis in vivo may have therapeutic applications in diseases or conditions where abnormal angiogenesis is part of the pathology.
  • This discovery provides novel therapies to treat such pathological conditions as growth of solid tumors, rheumatoid arthritis, atherosclerosis, fibroplasia, hemangioma, neovascular glaucoma, psoriasis, and diabetic retinopathy, which require angiogenesis for their progression.
  • IL-1 may also have
  • IL-1 Inhibited the proliferation of human endothelial cells in vitro in a dose-dependent manner, in vivo.
  • IL-1 when given systemically, inhibited the growth of B16 melanoma in syngeneic mice. This inhibition in tumor growth was related to a decrease in number of endothelial cells within the tumor and the loss of sites for radiolabeled bFGF to bind to the endothelial cells within the tumor.
  • Basic FGF is a potent stimulator of
  • IL-1 on angiogenesis may include Its capacity to decrease the number of receptors for bFGF on the endothelial cells, thus limiting bFGF stimulation of growth.
  • IL-1 ⁇ and ⁇ may inhibit angiogenesis through the down-regulation of the cellular receptor of bFGF.
  • IL-1 ⁇ or ⁇ may inhibit angiogenesis through the down-regulation of the cellular receptor of bFGF.
  • IL-1 ⁇ or ⁇ may inhibit angiogenesis through the down-regulation of the cellular receptor of bFGF.
  • IL-1 ⁇ or ⁇ may inhibit angiogenesis through the down-regulation of the cellular receptor of bFGF.
  • IL-1 ⁇ or ⁇ to cultures of rabbit chondrocytes, which were stimulated by bFGF, inhibited the growth of the chondrocytes (Example 1).
  • IL-1 decreased the number of bFGF receptors of the chondrocytes while decreasing the Kd (increasing the affinity) of the remaining receptors.
  • Kd increasing the affinity
  • IL-1 ⁇ inhibited tumor growth in a dose-dependent manner when given locally (intratumorally) or systemically (intraperitoneally, intramuscularly or intradermally). It was observed that after 1 or 2 injections of IL-1 ⁇ the tumor mass contained less blood.
  • Example 3 shows that a monoclonal antibody which neutralized the activity of bFGF inhibits the growth of B16 tumors.
  • Example 4 shows that the blood volume of IL-1 ⁇ -treated tumors was significantly less than sham-treated tumors and that the number of endothelial cells from IL-1 ⁇ -treated tumors was less than the number of endothelial cells from sham-treated tumors. Finally, bFGF-stimulated growth of human endothelial cells was inhibited by human IL-1 ⁇ (Example 5).
  • IL-1 ⁇ inhibits the growth of endothelial cells and angiogenesis in the B16 melanoma model, and thereby inhibits the B16 melanoma, which, in part, requires bFGF and bFGF-mediated angiogenesis for its growth.
  • the mechanism of inhibition of angiogenesis in the B16 tumors may be similar to the situation in the rabbit chondrocyte model, i.e., a decrease in the number of bFGF cell surface receptors.
  • Our findings indicate that there is a decrease in the binding of 125 I-labelled bFGF to B16 tumor sections from mice treated in vivo with IL-1 ⁇ .
  • the binding of 125 I-label led bFGF is associated primarily with the endothelial cells within B16 tumors and not the B16 melanoma cells.
  • IL-1 ⁇ may regulate the receptors of bFGF on endothelial cells in vivo and this down-regulation in bFGF receptor levels may inhibit the angiogenic response to bFGF and may contribute to the IL-1-mediated inhibition of angiogenesis and tumor growth.
  • B16 mouse melanoma cells in culture do not express high affinity binding sites for FGF
  • sections of B16 tumors grown in syngeneic mice show numerous patches of high affinity sites. Using immunostaining, we have demonstrated that these patches lie over areas that stain for Factor VIII, a marker for endothelial cells. This suggests that the FGF sites reside on the
  • IL-1 ⁇ i Decreases the Number of bFGF Receptors and Blocks the Mitogenic Effect of bFGF on Rabbit Chondrocytes
  • chondrocytes with IL-1 ⁇ was found to induce a down-regulation of the number of functional bFGF high affinity receptors.
  • IL-1 ⁇ Effect of IL-1 ⁇ on chondrocyte growth. Cultures used for these experiments were in logarithmic growth phase. Cultures were treated with IL-1 ⁇ , bFGF, or both, in DMEM and 5% FBS after the cells had been allowed to settle and attach for 48-72 hours in 6-well culture plates. At the appropriate times after addition of IL-1 ⁇ , bFGF, or both, the cells were detached with a trypsin-EDTA (0.05% trypsin, 0.53 mM EDTA) solution. Cells were washed twice with phosphate buffered saline (PBS), pH 7.4. Cell counts were made using a coulter counter.
  • PBS phosphate buffered saline
  • Table 1 shows that bFGF at 10 ng/mL is a mltogen for rabbit articular chondrocytes.
  • IL-1 ⁇ at 10 units/mL had the expected negative effect on growth (Huang et al. (1987) Mol. Biol. Med. 4:169-181).
  • the mitogenic effect of bFGF was entirely blocked.
  • the inhibitory effect of IL-1 ⁇ appeared to have effectively negated all the mitogenic activity of bFGF.
  • IL-1 (10 unit/mL) 3.87 ( ⁇ 0.03) 5.35 ( ⁇ 0.06) bFGF (10 ng/mL) 7.07 ( ⁇ 0.25) 9.79 ( ⁇ 0.4) bFGF (10 ng/mL) +
  • bFGF receptor binding assay The bFGF receptor binding assay. bFGF was iodinated using a modification of the lactoperoxidase procedure reported by
  • the medium was removed and the cells washed with cold PBS to determine free ligand.
  • the cells were washed twice with 2 M NaCl in 20 mM HEPES at pH 7.5 to remove low affinity binding and then with 2 M NaCl in 20 mM sodium acetate at pH 4.0 to collect high affinity binding.
  • 24-well plates was 2.5 ⁇ 10 5 .
  • the low affinity binding was variable and estimates of the binding parameters by non-linear regression ranged from 100-600 nM for Kd and from 21-250 ⁇ 10 6 sites/cell.
  • the high affinity binding was much more reproducible and yielded estimates of 59 ⁇ 4.2 pM for Kd and 8.72 ⁇ 0.24 fmoles/well (21,000 sites/cell).
  • IL-1 ⁇ Decreases the Number and Increases the Affi ni ty
  • IL-1 can i nhi bi t the biologi cal acti on of bFGF , i n part, by down-regulation of the level of functional bFGF high affinity receptors on a cell.
  • mice Female C57BL/6 mice (7-12 weeks old, viral antibody free) were purchased from Charles River.
  • B16 melanoma cells were obtained from the National Cancer Institute (NCI) Tumor Repository, Frederick, MD, and were negative for viruses by mouse antibody production (MAP) testing and were mycoplasma free.
  • NCI National Cancer Institute
  • MAP mouse antibody production
  • the cells were maintained in vitro in RPMI 1640 (Gibco, Grand Island, NY) supplemented with 10% FCS (Hyclone, Logan, UT).
  • IL-1 Preparations The recombinant human and murine IL-1 ⁇ were prepared through the use of an expression system in E. coli and purified by the means of ion exchange and gel filtration chromatography (Huang et al. (1988) Mol. Blol. Med. 4:169: Huang et al. (1988) J. Immunol. 140:3838).
  • the biological activity, evaluated in the murine thymocyte assay was between 1-2 ⁇ 10 7 units/mg for human IL-1 ⁇ and 7-10 ⁇ 10 7 units/mg for murine IL-1 ⁇ .
  • endotoxin levels were 3-10 ng/mg of protein as determined by the QCL 1000 Limulus, amebocyte assay (MA Bioproducts, Walkerville, MD).
  • IL-1 ⁇ was diluted with D-PBS (Gibco) containing 0.5% normal C57BL/6 serum).
  • Tumor Therapy Experiments. The tumor cells used for transplantation were resuspended in PBS at the concentration of 5 ⁇ 10 6 cells/mL. Mice were injected intradermally on the ventral surface with 0.1 mL of the cell suspension. At this
  • IL-1 ⁇ intramuscularly
  • ITU intramuscularly
  • Control mice were injected with the diluent according to the same schedule as the IL-1 ⁇ -treated mice.
  • Tumor weight (mg) was calculated by the formula 0.5 ⁇ (W 2 ⁇ L 2 ), where W and L represent the width (mm) and length (mm) of the tumor.
  • Percent inhibition of tumor growth (1-T/C) 100%, where T and C represent the mean tumor weight of the treated and control groups.
  • the Student's t-test was used for statistical analysis using the Balance software program (Elsevier Scientific Software, Amsterdam, Netherlands).
  • IL-1 ⁇ inhibits the growth of B16 melanoma in vivo in a dose-dependent manner when given intratumorally (Table 3 and 4). IL-1 ⁇ also significantly inhibited the growth of B16 melanoma when given either intradermally or intramuscularly (Table 5). These results indicate that IL-1 ⁇ has antitumor properties. Table 3
  • IL-1 ⁇ was administered ITU once a day for 7 days from day 9 to day 15.
  • IL-1 ⁇ was administered ITU once a day for 7 days from day 8 to day 14. Inhibition was calculated on day 15.
  • IL-1 ⁇ was administered by various routes once a day for 7 days from day 10 to day 14 at a daily dose of 30 ⁇ g/mouse. Inhibition was calculated on day
  • control groups * p ⁇ 0.05 and *** p ⁇ 0.001.
  • control group ⁇ 100 (%).
  • B16 Melanoma Growth Is Inhibited by bFGF-neutralizing Monoclonal Antibodies The effect of bFGF-specific mAbs was also tested in the mouse B16 melanoma model.
  • Female C57BL/6 mice (N 5) weighing 18 to 20 g were injected intradermally (ID) with 1 ⁇ 10 5 B16 melanoma cells (ATCC, Rockville, MD) on day 0.
  • DG2 monoclonal antibody to bFGF 5 ⁇ g/injection
  • MOPC-21 a control murine monoclonal antibody
  • murine recombinant IL-1 ⁇ 3 ⁇ g/injection
  • vehicle PBS
  • DG2 and IL-1 ⁇ inhibited the growth of the B16 melanoma tumor in the mouse.
  • DG2 monoclonal antibody is described in the commonly assigned application of Reilly et al.
  • DG2 is produced by hybridoma cell designated DG2 which is on deposit in ATCC under accession number HB10202.
  • the results show that DG2, a monoclonal antibody which inhibits the in vivo angiogenic response in a rat kidney capsule angiogenesis model, as described in Reilly et al., also inhibits the growth of B16 melanoma in vivo.
  • the results suggest that growth of B16 melanoma is dependent, in part, on bFGF-medlated angiogenesis.
  • IL-1 ⁇ decreases blood volume and the number of endothelial cells within B16 melanomas.
  • Angiogenesis is the process of new capillary formation which involves the directional mobilization, cellular proliferation, and canalization of endothelial cells.
  • Angiogenesis requires factors including proteins produced by cells to orchestrate these processes. One of these proteins is bFGF.
  • An antibody that neutralizes bFGF's angiogenic activities also inhibits the growth of B16 melanoma (Table 6), which indicates that B16 melanoma requires, in part, bFGF-mediated angiogenesis for its growth. If IL-1 ⁇ is inhibiting the growth of B16 tumor by inhibiting angiogenesis then there should be less blood volume and fewer endothelial cells within the tumors of IL-1B treated mice.
  • mice were injected intradermally with B16 cells (5 ⁇ 10 5 ). Ten days later, when the tumors were approximately 150 mg, murine IL-1 ⁇ (10 ⁇ g/mouse/day) or PBS was injected intradermally for 3 consecutive days. On the fourth day the mice were bled from the retro-orbital plexus and sacrificed. Tumors were excised, weighed and homogenized in PBS at 50 mg/nil.. The amount of hemoglobulin (Hg) per mL of blood was determined for each mouse using a SigmaTM hemoglobulin assay. One mL of tumor homogenate was washed 3 X in PBS by
  • concentration of the lysates was determined using the SigmaTM hemoglobulin assay.
  • the blood volume/gram of tumor was
  • IL-1 ⁇ Decreases the Vol ume of Blood i n B16 Melanoma
  • mice C57BL/6 mice were injected intradermally with B16 cells (5 ⁇ 10 5 ) and 10 days later, when the tumors were approximately 350 mg, treatment was started.
  • a group of 5 mice received intradermal daily injections of either PBS or IL-1 ⁇ (10 ⁇ g/injection) for 3 consecutive days.
  • the mice were injected intratumorally with acetylated low density lipoprotein (LDL) labeled with
  • the concentration of protein/mL of homogenate was determined for each homogenate using BCA protein assay (Pierce, Rockford, IL).
  • Table 8 systemic treatment of mice with IL-1 ⁇ decreased the number of endothelial cells within the B16 tumor by 43%.
  • IL-1 ⁇ Decreases the Number of Endothelial
  • IL-1 ⁇ Inhibits bFGF-mediated Growth of Human Endothelial Cells in vitro Human endothelial cells from saphenous veins (1 ⁇ 10 4 ) were cultured on day 1 in RPMI 1640 (Gibco, Grand Island, NY) supplemented with 0.5% fetal calf serum and 100 ng/mL of bFGF, with and without IL-1 ⁇ , in 48-well multi-well plates (Costar, Cambridge, MA), and their growth was monitored by cell counts on days 3, 5, and 7 (Table 10).
  • IL-1 ⁇ (100 ng/mL) 3 1.1 ⁇ 10 4 0
  • IL-1 ⁇ (1000 ng/mL) 7 1.5 ⁇ 10 4 61
  • Endothelial cells were treated with 100 ng/mL bFGF on day 1.
  • IL-1 ⁇ inhibited the growth of the human endothelial cells.
  • IL-1 ⁇ was not directly toxic to endothelial cells since the number of viable cells in the presence of IL-1 ⁇ was equal to or greater than the number of cells plated on day 1.
  • B16 growth is under the control of angiogenic factors, including bFGF, that IL-1 ⁇ decreases the blood volume within B16 tumors and decreases the number of endothelial cells within the tumor and that IL-1 ⁇ inhibits the proliferation of human endothelial cells in vitro.
  • angiogenic factors including bFGF
  • IL-1 can be administered as a sterile, nonpyrogenic
  • the aqueous parenteral vehicle could be, for example. Sterile Water for Injection USP, 0.9% Sodium
  • compositions of the present invention comprise an effective amount of purified IL-1 ⁇ and a pharmaceutically acceptable carrier such as listed above, and optionally
  • IL-1 may be prepared in a stable formulation ready for administration, or for dilution in an appropriate intravenous solution.
  • IL-1 may be formulated, for example, as a sterile lyophilized powder to be reconstituted aseptically as a buffered solution.
  • IL-1 may be formulated in combination with at least one additional antiangiogenic factor, such as the DG2 monoclonal antibody along with a pharmaceutically acceptable carrier.
  • ingredient, and its mode and the route of administration the age, health, and weight of the recipient; the nature and extent of symptoms; the kind of concurrent treatment and frequency of treatment; and the effect desired.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
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  • Gastroenterology & Hepatology (AREA)
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Abstract

L'invention décrit l'utilisation de IL-1 et, de préférence, IL-1beta, seules ou combinées à un ou plusieurs facteurs supplémentaires anti-angiogéniques, pour inhiber l'angiogénèse et obtenir des résultats thérapeutiques dans des états pathologiques provoqués par l'angiogénèse et, particulièrement, des états pathologiques angiogéniques provoqués par le facteur de croissance des fibroblastes de base, tels que des tumeurs solides, l'arthrite, l'athérosclérose, le psoriasis et la rétinopathie diabétique.
PCT/US1990/007220 1990-12-14 1990-12-14 Inhibition de l'angiogenese par il-1 WO1992010210A1 (fr)

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PCT/US1990/007220 WO1992010210A1 (fr) 1990-12-14 1990-12-14 Inhibition de l'angiogenese par il-1

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5560908A (en) * 1993-01-22 1996-10-01 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Therapeutic agent for NIDDM
WO1998000183A2 (fr) * 1996-06-28 1998-01-08 Shaw, Robert, Francis Procedes et compositions de traitement et de guerison des defauts ou lesions dans un cartilage ou un os au moyen d'une barriere fonctionnelle
US5997868A (en) * 1993-10-18 1999-12-07 North Shore University Hospital Research Corporation Inhibition of scatter factor for blocking angiogenesis
US7566772B2 (en) 2005-01-26 2009-07-28 Amgen Fremont Inc. Antibodies against interleukin-1β
WO2010128407A2 (fr) 2009-05-05 2010-11-11 Novimmune S.A. Anticorps anti-il-17f et leurs méthodes d'utilisation
EP1725261B1 (fr) * 2004-02-17 2011-01-26 Schering Corporation Utilisation d'agonistes et d'antagonistes d'interleukine-33 (il-33)
US8609090B2 (en) 2003-07-18 2013-12-17 Amgen Inc. Specific binding agents to hepatocyte growth factor
WO2018049261A1 (fr) 2016-09-09 2018-03-15 Icellhealth Consulting Llc Virus oncolytique exprimant des modulateurs du point de contrôle immunitaire

Citations (4)

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US4444744A (en) * 1980-03-03 1984-04-24 Goldenberg Milton David Tumor localization and therapy with labeled antibodies to cell surface antigens
US4785079A (en) * 1984-11-09 1988-11-15 The Salk Institute For Biological Studies Isolation of fibroblast growth factor
US4816436A (en) * 1986-10-29 1989-03-28 Immunex Corporation Anti-arthritic use of interleukin-1 proteins
US4923696A (en) * 1987-05-04 1990-05-08 Baylor College Of Medicine Method to prepare a neurotrophic composition

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4444744A (en) * 1980-03-03 1984-04-24 Goldenberg Milton David Tumor localization and therapy with labeled antibodies to cell surface antigens
US4785079A (en) * 1984-11-09 1988-11-15 The Salk Institute For Biological Studies Isolation of fibroblast growth factor
US4816436A (en) * 1986-10-29 1989-03-28 Immunex Corporation Anti-arthritic use of interleukin-1 proteins
US4923696A (en) * 1987-05-04 1990-05-08 Baylor College Of Medicine Method to prepare a neurotrophic composition

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FEBS LETTER, Volume 223, No. 2, issued November 1987, HUANG et al., "Muteins of Human Interleukin-1 that Show Enhanced Bioactivities", pages 294-298. *
JAPANESE JOURNAL OF CANCER RESEARCH , Volume 77, No. 8, issued August 1986, NAKAMURA et al., "Antitumor Effect of Recombinant Human Interleukin 1 Alpha Against Murine Syngeneic Tumors", pages 767-773. *
SCIENCE, Volume 221, No. 4612, issued 19 August 1983, FOLKMAN et al., "Angiogenesis Inhibition and Tumor Regression Caused by Heparin or a Heparin Fragment in the Presence of Cortisone", pages 719-725. *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5560908A (en) * 1993-01-22 1996-10-01 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Therapeutic agent for NIDDM
US5997868A (en) * 1993-10-18 1999-12-07 North Shore University Hospital Research Corporation Inhibition of scatter factor for blocking angiogenesis
WO1998000183A2 (fr) * 1996-06-28 1998-01-08 Shaw, Robert, Francis Procedes et compositions de traitement et de guerison des defauts ou lesions dans un cartilage ou un os au moyen d'une barriere fonctionnelle
WO1998000183A3 (fr) * 1996-06-28 1998-02-12 Shaw Robert F Procedes et compositions de traitement et de guerison des defauts ou lesions dans un cartilage ou un os au moyen d'une barriere fonctionnelle
US8609090B2 (en) 2003-07-18 2013-12-17 Amgen Inc. Specific binding agents to hepatocyte growth factor
EP1725261B1 (fr) * 2004-02-17 2011-01-26 Schering Corporation Utilisation d'agonistes et d'antagonistes d'interleukine-33 (il-33)
US9970944B2 (en) 2004-02-17 2018-05-15 Merck Sharp & Dohme Corp. Methods of modulating cytokine activity; related reagents
US7566772B2 (en) 2005-01-26 2009-07-28 Amgen Fremont Inc. Antibodies against interleukin-1β
US7964193B2 (en) 2005-01-26 2011-06-21 Amgen Fremont Inc. Antibodies against interleukin-1 β
WO2010128407A2 (fr) 2009-05-05 2010-11-11 Novimmune S.A. Anticorps anti-il-17f et leurs méthodes d'utilisation
WO2018049261A1 (fr) 2016-09-09 2018-03-15 Icellhealth Consulting Llc Virus oncolytique exprimant des modulateurs du point de contrôle immunitaire
WO2018049248A1 (fr) 2016-09-09 2018-03-15 Icellhealth Consulting Llc Virus oncolytique équipé de molécules d'engagement bispécifiques

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