GB2189393A - Combination therapy using interleukin-2 and glucocorticoid - Google Patents
Combination therapy using interleukin-2 and glucocorticoid Download PDFInfo
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- 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
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Abstract
Anti-tumor activity in mammals can be combatted by administering to the mammalian host a synergistically effective amount of human IL-2 and one or more glucocorticoids in combination. The composition of IL-2 and glucocorticoid(s) may be prepared in vitro or administered separately to the host. The composition is useful for treating such cancers as sarcoma. The glucocorticoid is preferably dexamethasone.
Description
SPECIFICATION
Combination Therapy Using Interleukin-2 and Glucocorticoid
This invention relates to a combination of human interleukin-2 (IL-2) and one or more steroids and the use of this combination as an anti-tumor therapeutic agent.
Interleukin-2, a lymphokine which is produced by normal peripherai blood lymphocytes and induces proliferation of antigen or mitogen stimulated T cells after exposure to plant lectins, antigens, or other stimuli, was first described by Morgan, D. A., et at., Science (1976), 193:1007-1008. Then called T cell growth factor because of its ability to induce proliferation of stimulated T lymphocytes, it is now recognized that in addition to its growth factor properties, it modulates a variety of functions of immune system cells in vitro and in vivo and has been renamed interleukin-2 (IL-2).
IL-2 was initially made by cultivating human peripheral blood lymphocytes (PBL) or other IL-2- producing cell lines. See, for example, U.S. Patent No.4,401,756. Recombinant DNA technology has provided an alternative to PBLs and cell lines for producing IL-2. Taniguchi, T. et al., Nature (1983), 302:305--310 and Devos, R., NucleicAcids Research (1983), 11:4307-4323 have reported cloning the human IL-2 gene and expressing it in microorganisms.
U.S. Patent No.4,518,584 describes muteins of IL-2 in which the cysteine normally occurring at position 125 of the wild-type or native molecule has been replaced with a neutral amino acid, such as serine. These muteins possess biological activity. U.S. Patent No. 4,604,377 discloses an IL-2 composition suitable for reconstituting in a pharmaceutically acceptable aqueous vehicle composed of oxidized microbially produced recombinant IL-2. The IL-2 is noted as useful in combination with cytotoxic chemotherapy or irradiation or surgery in the treatment of malignant orpre-malignant diseases in a direct therapeutic or adjuvant setting or in combination with other immune-modulating drugs, lymphokines (e.g., IL-l, IL-3,
CSF-1 and IFNs), or naturally occurring or inducible anti-cellular toxins in treating malignant diseases.
Various therapeutic applications of human IL-2 have been investigated and reported by S. Rosenberg and colleagues (see Mule et al., Science (1984), 225:1487 and S. Rosenberg et al., New EnglandJournal of Medicine(1985), 313:1485--1492, for example).
Combination chemotherapy using two or more anti-cancer drugs to treat malignant tumors in humans is currently in use in research and in the clinic. The anti-cancer drugs may be antimetabolites, alkylating agents, antibiotics, general poisons, etc. Combinations of drugs are administered in an attempt to obtain a synergistic cytotoxic effect on most cancers, e.g., carcinomas, melanomas, lymphomas and saccomas, and to reduce or eliminate emergence of drug-resistant cells and to reduce side effects to each drug.
For example, it is known that IL-2 may be used with IFN-y to treat tumor-bearing hosts with synergistic results (European Patent Publication 149,551 published July 1985 (Genentech) and German Patent
Publication 3411184 published October 1985 (Deut Roten Kreuzes)) or with augmentation of natural killer activity (Svedersky et al., J. Immunol. (1984), 133:714718 and Shalaby et al., J. Interferon Res. (1985), 5:571-581). In addition, U.S. Statutory Invention Reg. No.H22, published February 4, 1986 to Creasey et al., discloses a composition exhibiting a synergistic cytotoxic effect in combination therapy of certain breast cancer and myeloma cell lines using synergistically effective amounts of 5-fluorouracil and human recombinant beta-interferon.
Dr. S. Rosenberg of the NIH observed in the spring of 1985 that in one patient who was receiving IL-2 and corticosteroids together, the corticosteroids being administered to treat acute spinal cord compression, the IL-2 related toxicity was noticably decreased by the concomitant use of the corticosteroids. Most practitioners in the field would expect that the steroid would also block the anti-tumor activity of the IL-2.
The present invention relates to the unexpected discoveries that IL-2-induced tumor regression is not blocked by concomitant administration of glucocorticoids, and that at specific doses of glucocorticoids with
IL-2, there is a synergistic anti-tumor effect.
Accordingly, the present invention provides a composition suitable for parenteral or subcutaneous administration to mammalian hosts for the prophylaxis or therapeutic treatment of cancer comprising a mixture of human IL-2 and one or more glucocorticoids in synergistically effective amounts.
The invention also provides the use of IL-2 and one or more glucocorticoids in providing medication for the prophylaxis or therapeutic treatment of cancer in mammalian hosts.
In another aspect the invention provides a mixture of human IL-2 and one or more glucocorticoids for use in the prophylaxis or therapeutic treatment of cancer in mammalian hosts.
Also included in the invention is a method of making a formulation for the prophylaxis or treatment of cancer comprising formulating together human IL-2 and one or more glucocorticoids.
Thus, the invention enables a method for therapeutic treatment of cancer in mammalian hosts comprising administering a synergistically effective amount of IL-2 and one or more glucocorticoids to the host.
Preferably, the IL-2 is a recombinant, microbially produced protein and the glucocorticoid is dexamethasone.
The combination of IL-2 and glucocorticoids provides a surprising synergism in treating cancer cells, and the glucocorticoids surprisingly decrease toxicity levels.
As used herein, the term "therapeutic" treatment refers to administration to the host of the IL-2 and steroid(s) after the host has contracted cancer, as determined by any means. The treatment is not considered therapeutic if after treatment a tumor appears or if an existing tumor burden is not eliminated or decreased. The effect of the dose will diminish with time, with from 3 to 7 days after the tumor is visible being typically the maximum period in which treatment of animals can be given, depending mainly on the type of tumor, dosage levels and type of route and schedule of administration.
As used herein, the term "cancer" refers to any neoplastic disorder, including such cellular disorders as, for example, renal cell cancer, Kaposi's sarcoma, chronic leukemia, breast cancer, sarcoma, ovarian carcinoma, rectal cancer, throat cancer, melanoma, colon cancer, bladder cancer, mastocytoma, lung cancer and gast diintestinal or stomach cancer. Preferably, the cancer is sarcoma.
As used herein, the term "synergistically effective amount" as applied to IL-2 and the glucocorticoid(s)
refers to the amount of each component of the mixture which is effective for survival of the host and which
produces a survival level which does not intersect, in a dose-response plot of the dose of glucocorticoid versus dose of IL-2 versus host survival, either the dose glucocorticoid axis or dose IL-2 axis. The
dose-response curve used to determine synergy herein is more fully described by Sande et al., p.
1080--1105 in A. Goodman et al., ed., The Pharmacological Basis of Therapeutics, MacMillan Publishing
Co., Inc., New York (1980). For purposes of synergy, survival is defined as survival of the host after 14 days from the date of tumor implantation into the host. The optimum synergistic amounts can be determined,
using a 95% confidence limit, by varying factors such as dose level, schedule and response, and using a
computer-generated model which generates isobolograms from the dose response curves for various combinations of the IL-2 and glucocorticoid(s). The highest survival rates on the dose-response curve
correlate with the optimum dosage levels.
As used herein, the term "recombinant" refers to IL-2 produced by recombinant DNA techniques wherein generally the gene coding for the IL-2 is cloned by known recombinant DNA technology. For
example, by using the human IL-2 messenger RNA as a template, the gene showing complementarity to the
human 11-2 messenger RNA is inserted into a suitable vector DNA such as an E. coli plasmid to obtain a
recombinant plasmid and the plasmid is used to transform a suitable host. The gene is expressed in the
host to produce the recombinant protein. Examples of suitable recombinant plasmids for this purpose
include pBR322, pCR1, pMB9 and pSC1. The transformed host may be eucaryotic or procaryotic.
As used herein, the term "pharmaceutically acceptable" refers to a carrier medium which does not
interfere with the effectiveness of the biological activity of the active ingredients and which is not toxic to the hosts to which it is administered.
The method of this invention involves administering to a mammalian host, preferably a human host, a
synergistically effective amount of human IL-2 and one or more glucocorticoids. The IL-2 and
glucocorticoid(s) may be combined in vitro before administration or separately administered to the host, in
either order or simultaneously, with any second administration generally within from one minute to one
hour of the first administration.
The administration(s) may take place by any suitable technique, including subcutaneous and parenteral
administration, preferably parenteral. Examples of parenteral administration include intravenous,
intraarterial, intramuscular, and intraperitoneal, with intraperitoneal administration(s) being preferred.
The dose and dosage regimen will depend mainly on whetherthe IL-2 and glucocorticoid(s) are being
administered separately or as a mixture, the type of cancer, the patient, and the patient's history. The
amount must be effective to achieve a tumor reduction which is synergistic. The doses may be single doses or multiple doses. If multiple doses are employed, as preferred, the frequency of administration will
depend, for example, on the type of host and type of cancer, dosage amounts, etc. For some types of
cancers or cancer lines, daily administration may be effective, whereas for others, administration every other day or every third day may be effective, but daily administration ineffective. The practitioner will be able to ascertain upon routine experimentation which route of administration and frequency of administration are most effective in any particular case.
The dosage amount which appears to be most effective herein is one which results in no tumor appearance and is not toxic to the host. In addition, the dose of glucocorticoids cannot be so large as to
inhibit the anti-tumor activity of the IL-2. This optimum level will depend on many factors, for example, on the type of host and type of cancer, route, schedule and sequence of administration, existing tumor burden, the type of IL-2 and glucocorticoid, and the definition of toxicity. Toxicity to the host may be defined by the extent and type of side effects or by the amount of body weight loss or by death after a certain period of time.If body weight loss is the criterion for toxicity, typically a loss of from 1020% by weight will be tolerated, with greaterthan 20% loss being consideredtoxic. If body weight loss of greater than 20% is
considered toxic, if the host is murine, if the route of administration is intraperitoneal via a mixture prepared in vitro and is every day or every other day, the dosage level at each administration of recombinant,
microbially produced IL-2 and dexamethasone is preferably about 4--30 pg dexamethasone (more
preferably about 510 pig), and about 3-50 pg IL-2 (more preferably 10301l9).
For parenteral administration the IL-2 and glucocorticoid(s) will generally be formulated in a unit
dosage injectable form (solution, suspension, emulsion), preferably in a pharmaceutically acceptable
carrier medium which is inherently non-toxic and non-therapeutic. Examples of such vehicles include water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as fixed oils and ethyl oleate may also be used. The carrier medium may contain minor amounts of
additives such as substances which enhance isotonicity and chemical stability, e.g., buffers and preservatives. The IL-2 and glucocorticoid(s) will typicaliy be formulated in such carriers at a concentration of about 0.1 mg/ml to 100 mg/ml.
Alternatively, the IL-2 and glucocorticoids may be made into a sterile, stable lyophilized formulation in which the purified IL-2 and glucocorticoid(s) are admixed with a water-soluble carrier such as mannitol, which provides bulk, and a sufficient amount of sodium dodecyl sulfate to ensure the solubility of the recombinant IL-2 in water. The formulation is suitable for reconstitution in aqueous injections for parenteral administration and it is stable and well-tolerated in human patients. The formulation method is morecompletely described in U.S. Patent No.4,604,377.
As mentioned above, the human 1L-2 herein may be any IL-2 from a human source, but most preferably is recombinant IL-2. The recombinant IL-2 may be obtained as described by Taniguchi et al., Nature, 302:305--310 (1983) and Devos, Nucleic Acids Research, 11:4307--4323 (1983) by cloning the human lL-2 gene and expressing it in microorganisms. It may also be an IL-2 mutein as described in U.S. Patent No.
4,518,584, in which the cysteine normaily occurring at position 125 of the wild-type or native molecule has been replaced by a neutral amino acid such as serine.
Preferably, the IL-2 is an unglycosylated protein which is produced by a microorganism which has been transformed with the human IL-2 DNA sequence or a modified human IL-2 DNA sequence which encodes a protein with an amino acid sequence at least substantially identical to the amino acid sequence of native human IL-2, including the disulfide bond of the cysteines at positions 58 and 105, and has biological activity which is common to native human IL-2. Substantial identity of amino acid sequences means the sequences are identical or differ by one or more amino acid alterations (deletions, additions, substitutions) which do not cause an adverse functional dissimilarity between the synthetic protein and native human IL-2.
Examples of IL-2 proteins with such properties include those described by European Patent Publication Nos.
91,539 and 88,195 and by U.S. Patent 4,518,584, supra. Most preferably, the IL-2 is the des-aIai-lL-2seri2s mutein in which the initial terminal alanine is deleted and the cysteine at position 125 is replaced by a serine residue.
The IL-2 may be produced and purified by the method described in U.S. Patent No.4,604,377.
In an alternative formulation, described in PCT Publication No. W087/00056, hydrophobic protein may be soiubilized, not by a detergent, but by reacting the protein with an activated homopolymer selected from polyethylene glycol, polypropylene glycol or polybutylene glycol, said homopolymer having a molecular weight of from 500 to 20,000 daltons, preferably 2000 to 10,000 daltons. The homopolymer is activated by conjugation with a coupling agent having terminal groups reactive with both the free amino or thiol groups of the protein and the hydroxyl group of the homopolymer. Examples of such coupling agents include hydroxynitrobenzene sulfonic ester, cyanuric acid chloride, and N-hydroxysuccinimide. This modification eliminates the necessity for adding detergents to solubiiize the protein at physiological pH.The protein is then formulated directly with water-soluble carrier and buffer as described above, and the formulation may be lyophilized and the lyophilized mixture reconstituted as described above.
The glucocorticoid which may be employed herein may be any steroid which is classified as a glucocorticoid, including, e.g., beclomethasone salts, betamethasone salts, clobetasol salts, clobetasone butyrate, cortisone acetate, cortivazol, deoxycortone acetate, deoxycortone pivalate, desonide, desoxymethasone, dexamethasone, diflucortolone valerate, fluclorolone acetonide, fludrocortisone acetate, flumethasone pivalate, fluocinolone acetonide, fluocinonide, fluocortolone, fluorometholone, fiurandrenolone, halcinonide, hydrocortisone, medrysone, meprednisone, methylprednisolone, paramethasone acetate, prednisone, prednylidene and triamcinolone. In addition, such fluorinated steroids as cronolone, fluoxymesterone and fluprednisolone. Preferably, the glucocorticoid is dexamethasone.
The various aspects of the invention are further described by the following examples, which are not intended to limit the invention in any manner. In these examples all parts for solids are by weight and all
percentages for liquids and gases are by volume, unless otherwise noted, and all temperatures are given in degrees Celsius.
EXAMPLE 1
A. General Treatment
Mice
Female CD1 mice which were all 6--8 weeks old were employed in the in vivo tests as syngeneic hosts for Meth Atumors.
IL-2
The recombinant IL-2 employed in this example was des-ala, lL-2ser,2s. The amino acid sequence of this
IL-2 differs from the amino acid sequence of native human IL-2 in that it lacks the initial alanine of the native
molecule, and the cysteine at position 125 has been changed to serine. Samples of E. colithat produce this
IL-2 have been deposited by Cetus Corporation in the American Type Culture Collection, 12301 Parklawn
Drive, Rockville, Md, USA on September 1983 under accession number 39,452 and on March 6, 1984
under accession number 39,626 under the provisions of the Budapest Treaty.
The IL-2 was processed and purified as described in the text and Figure 1 of the U.S. Patent No.
4,604,377, except that the oxidation was carried out using copper chloride, as described in U.S. Patent No.
4,572,798 rather than o-iodosobenzoate. When the IL-2 was recovered from the chromatography step(s) it
was lyophilized and resuspended in a neutral aqueous buffer containing the reducing agent (DTT) to keep
the IL-2 in a reduced state and a solubilizing agent to keep it in solution. The purity of the recombinant IL-2
after the chromatography step(s) was at least a bout 95% and the I L-2 contained less than about 0.02 ng/m I endotoxin as determined by the Limulus ameboryte assay.
The purified IL-2 was formulated at a concentration of 0.3 mg/ml with 50 mg/ml mannitol and an
effective amount of SDS as necessary.
In an alternative formulation, the IL-2 was formulated as by reaction with polyethylene glycol (PEG) which was conjugated to the IL-2 using N-hydroxysuccinimide. The conjugated protein was formulated
directly in water (hereinafter called IL-2-PEG).
Steroid
The glucocorticoid employed herein as commercially available dexamethasone.
Cancer Cell Line and Tumor Injections
The target cells employed were Methacholanthene-A (Meth A)-induced sarcoma (Balb/c) from
Sloan-Kettering. These cells were implanted subcutaneously into the neck of the mouse host
B. Results
Table I indicates the results obtained when IL-2 alone, dexamethasone alone, and various mixtures of
IL-2 and dexamethasone (prepared in vitro) were administered intraperitoneallyto groups of two mice beginning one day after tumor implantation and continuing every day for seven days, with measurements made on the seventh day. The control was injected with PBS.
TABLE I
Dexamethasone
Control 10 pg IL-2 30 pg IL-2 PBS Control
Tumor Mouse Tumor Mouse Tumor Mouse Tumor Mouse
Vol Wt Vol Wt Vol Wt Vol Wt
(mm3) (g) (mm3) (g) (mm3) (g) (mm3) (g) 500 g 140+23 18.2 157+67 17.6 106+39 18.1 - - Dexamethasone 50 g 373+94 19.5 132+41 19.8 38+5 18.6 - - Dexamethasone 5pg 1379+281 21.4 51+12 21.1 8+12 19.0 - - Dexamethasone
IL-2 Control - - 62+27 21.3 56+30 20.5 - - PBS Control - - - - - - 1236+233 22.4
Table II gives the same results when IL-2-PEG alone, dexamethasone alone, and various mixtures of 11-2 and dexamethasone (prepared in vitro) were administered under the same conditions, and results were obtained after 7 days from implantation.
TABLE II
Dexamethasone
Control 3 g IL-2-PEG PBS Control
Tumor Mouse Tumor Mouse Tumor Mouse
Vol Wt Vol Wt Vol Wt
(mm3) (9) (mm3) (g) (mm3) (g)
500 g Dexamethasone 461i71 19.0 261+12 19.5 50 pg Dexamethasone 1398+395 20.9 37+25 20.1 - 5 g Dexamethasone 1875+320 22.7 14+11 20.0 IL-2-PEG Control - - 13+8 22.0 - - PBS Control - - - - 2649303 22.4
The results indicate that 5 pg of dexamethasone given daily along with 10--30 pg iL-2 was synergistic, and that a range can be defined which would cover all synergistically effective doses for IL-2 and proteins with activity similar to that of IL-2, for example, polyethylene glycol-modified IL-2.
The practitioner can predict that these results would apply to humans based on the known correlation between the IL-2 dose-related anti-tumor effect in animals and humans. The preclinical responses of IL-2 alone correlated to clinical responses of IL-2 to colon, lung, melanoma, renal cell carcinoma, and ovarian carcinoma.
EXAMPLE 2
Commercially available nude mice from Baltic strain implanted subcutaneously in the neck with
OVCAR-3, a human-derived ovarian cell line from the National Institutes of Health (Dr. Hamilton), and available from the American Type Culture Collection, Rockville, MD, were treated daily for seven days with
IL-2-PEG, dexamethasone or IL-2-PEG and dexamethasone, with the results indicated in Table III.
TABLE III
Treatment Number of Deaths per Day
Dexamethasone (50 pg per dose) 0/8
IL-2-PEG (1 pg per dose) and dexamethasone (50 pg per dose)* 2/8
IL-2-PEG (1 pg per dose) 6/8 *For the first injection the dexamethasone were administered first followed within the hour by the lL-2, and subsequent injections were with a mixture of IL-2 and dexamethasone. The same results were
obtained by mixing the dexamethasone and IL-2 initially before the first administration.
These results confirm that at equal doses of IL-2, animals receiving concurrent dexamethasone
demonstrated decreased signs of toxicity.
In summary, the present invention is seen to provide a combination of IL-2 and glucocorticoid(s) which
has anti-tumor activity and a lower toxicity than IL-2 alone in mammalian hosts. It is unexpected and an
obvious advantage that glucocorticoids also do not block the anti-tumor efficacy of IL-2 at moderate doses
and that glucocorticoids are synergistic with IL-2 at specific doses (physiologically relevant doses) in
regressing a Meth A-induced murinetumortransplanted into a syngeneic host.
Claims (16)
1. A composition suitable for parenteral or subcutaneous administration to mammalian hosts for the
prophylaxis ortherapeutictreatment of cancer comprising a mixture of human IL-2 and one or more
glucocorticoids in synergistically effective amounts.
2. A composition according to claim 1 further comprising a pharmaceutically acceptable carrier medium for the IL-2 and steroid(s).
3. A composition according to claim 1 or 2 wherein the IL-2 is recombinant and the cancer is sarcoma or ovarian cancer.
4. A composition according to any one of claims 1-3 wherein the IL-2 is des-ala-lL2ser25.
5. A composition according to any one of claims 14 wherein the glucocorticoid is dexamethasone.
6. The use of IL-2 and one or more glucocorticoids in providing medication for the prophylaxis or therapeutic treatment of cancer in mammalian hosts.
7. Human IL-2 and one or more glucocorticoids for use in the prophylaxis or therapeutic treatment of cancer.
8. The use of claim 6 or IL-2 and one or more glucocorticoids according to claim 7 wherein the IL-2 and glucocorticoid(s) are administered separately to the host.
9. The use of claim 6 or IL-2 and one or more glucocorticoids according to claim 7 wherein the IL-2 and glucocorticoid(s) are mixed in vitro prior to administration to the host.
10. The use of any one of claims 6,8 or 9 or IL-2 and one or more glucocorticoids according to any one of claims 7 to 9 wherein the cancer is sarcoma or ovarian cancer, the IL-2 is a recombinant mutein, and the glucocorticoid is dexamethasone.
11. The use of any one of claims 6,8,9 or 10 or IL-2 and one or more glucocorticoids according to any one of claims 7 to 10 wherein the IL-2 and glucocorticoid(s) are in admixture with a pharmaceuticaliy acceptable carrier medium prior to administration and the host is human.
12. A method of making a formulation for the prophylaxis or treatment of cancer comprising formulating together human IL-2 and one or more glucocorticoids.
13. A composition according to claim 1 and substantially as hereinbefore described.
14. A composition according to claim 1 and substantially as hereinbefore described in Example 1 or
Example 2.
15. The use of claim 6 and substantially as hereinbefore described.
16. The use of claim 6 and substantially as hereinbefore described in Example 1 or Example 2.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US85580286A | 1986-04-24 | 1986-04-24 |
Publications (2)
Publication Number | Publication Date |
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GB8709764D0 GB8709764D0 (en) | 1987-05-28 |
GB2189393A true GB2189393A (en) | 1987-10-28 |
Family
ID=25322100
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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GB08709764A Withdrawn GB2189393A (en) | 1986-04-24 | 1987-04-24 | Combination therapy using interleukin-2 and glucocorticoid |
Country Status (3)
Country | Link |
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AU (1) | AU7189087A (en) |
BE (1) | BE1001901A3 (en) |
GB (1) | GB2189393A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989009062A1 (en) * | 1988-03-28 | 1989-10-05 | Cetus Corporation | Combination therapy of il-2 and dtic for the treatment of melanoma |
US5089261A (en) * | 1989-01-23 | 1992-02-18 | Cetus Corporation | Preparation of a polymer/interleukin-2 conjugate |
EP1939216A1 (en) * | 2006-03-27 | 2008-07-02 | Smirnov, Mikhail Nikolaevich | Immunomodulating composition |
CN108778316A (en) * | 2016-03-16 | 2018-11-09 | 谢彦晖 | The polyethyleneglycol modified interleukin-22 of glucocorticosteroidsin in combination treats breathing problem |
-
1987
- 1987-04-23 BE BE8700444A patent/BE1001901A3/en not_active IP Right Cessation
- 1987-04-23 AU AU71890/87A patent/AU7189087A/en not_active Abandoned
- 1987-04-24 GB GB08709764A patent/GB2189393A/en not_active Withdrawn
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989009062A1 (en) * | 1988-03-28 | 1989-10-05 | Cetus Corporation | Combination therapy of il-2 and dtic for the treatment of melanoma |
US5089261A (en) * | 1989-01-23 | 1992-02-18 | Cetus Corporation | Preparation of a polymer/interleukin-2 conjugate |
EP1939216A1 (en) * | 2006-03-27 | 2008-07-02 | Smirnov, Mikhail Nikolaevich | Immunomodulating composition |
EP1939216A4 (en) * | 2006-03-27 | 2009-04-01 | Smirnov Mikhail Nikolaevich | Immunomodulating composition |
CN108778316A (en) * | 2016-03-16 | 2018-11-09 | 谢彦晖 | The polyethyleneglycol modified interleukin-22 of glucocorticosteroidsin in combination treats breathing problem |
EP3431096A4 (en) * | 2016-03-16 | 2020-01-15 | Xie, Yanhui | Glucocorticoid combined with polyethylene glycol-modified interleukin-2 for treating respiratory disease |
US10898576B2 (en) | 2016-03-16 | 2021-01-26 | Yanhui Xie | Glucocorticoid combined with polyethylene glycol-modified interleukin 2 for treating respiratory disease |
CN108778316B (en) * | 2016-03-16 | 2023-07-04 | 谢彦晖 | Treatment of respiratory diseases with glucocorticoid in combination with polyethylene glycol modified interleukin 2 |
Also Published As
Publication number | Publication date |
---|---|
AU7189087A (en) | 1987-10-29 |
GB8709764D0 (en) | 1987-05-28 |
BE1001901A3 (en) | 1990-04-10 |
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