GB2260902A - Interleukin-2 and tumour necrosis factor for treating bladder cancer - Google Patents
Interleukin-2 and tumour necrosis factor for treating bladder cancer Download PDFInfo
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- GB2260902A GB2260902A GB9119500A GB9119500A GB2260902A GB 2260902 A GB2260902 A GB 2260902A GB 9119500 A GB9119500 A GB 9119500A GB 9119500 A GB9119500 A GB 9119500A GB 2260902 A GB2260902 A GB 2260902A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- 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]
- A61K38/2013—IL-2
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Abstract
The use of IL-2 and TNF in the manufacture of a medicament for intravesical administration for the treatment of bladder cancer is described, together with pharmaceutical or veterinary formulations of IL-2 and TNF and the manufacture thereof. Products containing TNF and IL-2 as a combined preparation for simultaneous, separate or sequential use in the therapeutic or prophylactic treatment of bladder cancer by intravesical administration in human patients are also disclosed.
Description
COMPOSITION FOR USE IN TREATING BLADDER CANCER
The present invention relates to pharmaceutical (including veterinary pharmaceutical) formulations containing interleukin2 and tumour necrosis factor and for use in the treatment of bladder cancer.- Bladder cancer is a disease with a high mortality rate and which has hitherto defied all efforts to find a successful therapy. In particular, patients suffering from advanced transitional bladder carcinoma have a poor prognosis and no effective treatment for this group of patients is available.
Results from different chemotherapeutic/immunotheropeutic approaches generally have been disappointing.
Interleukin-2, a lymphokine which is produced by normal peripheral 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 al, 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 recognised 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).
Interleukin-2 was initially made by cultivating human peripheral blood lymphocytes (PBL) or other IL-2-producing cell lines. See, for example, US 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., Nucleic Acids Research (1983), 11:4307-4323 have reported cloning the human IL-2 gene and expressing it in microorganisms.
US Patent No. 4,518,584 describes and claims 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 or alanine. An oxidation-resistant mutein such as IL-2 which is biologically active may be prepared wherein each methionine residue of the protein from which the mutein is derived which methionine is susceptible to chloramine T or peroxide oxidation is replaced with a conservative amino acid such as alanine. These IL-2 muteins possess the biological activity of native IL-2. US Patents
Nos. 4,530,787 and 4,569,790 disclose and claim methods for purifying recombinant native IL-2 and muteins thereof, as well as purified forms of IL-2.
PCT W085/04328 discloses an IL-2 composition suitable for reconstituting in a pharmaceutically acceptable aqueous vehicle composed of oxidised 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 or pre-malignant diseases in a direct therapeutic or adjuvant setting or in combination with other immune-modulating drugs, lymphokines (e.g. IL-1, IL-3, CSF-1 and IFNs), or naturally occurring or inducible anti-cellular toxins in treating malignant diseases.
Tumour necrosis-factor (TNF) was first described by Carswell et al, PNAS (USA) (1975), 72:3666-3670 as an endotoxin-induced serum factor which causes necrosis of chemically transformed tumor cells when growing in mice.
Purified preparations of murine TNF have been tested against murine and human cell lines in vitro. K. Haranaka and N.
Satomi, Japan J. Exp. Med. (1981), 51:191. In contrast to normal cells, tumor cell lines from both species were susceptible to the cytotoxic activity of the mouse TNF.
Furthermore, the murine TNF was reported to be toxic against both human and mouse-transplanted tumors in nude mice. See K.
Haranaka et al, Int. J. Cancer (1984), 34:263-267. Human TNF is also known to be cytotoxic to neoplastic cells, and has been produced in recombinant form. See Pennica et al, Nature (1984), 312:724-729; Shirai et al, Nature (1985), 313:803-806;
Wang et al, Science (1985), 228:149-154.
The cloning of rabbit TNF is disclosed in EP 146,026 and EP 148,311. The cloning of human TNF having 151 and 155 amino acids (2 and 6 less than the native form) is disclosed in EP 155,549 and human TNF having 155 amino acids is disclosed in EP 158,286 and corresponding GB 2,158,829A. The cloning of mature
TNF (157 amino acids) and various modified forms (muteins) thereof is disclosed in EP 168,214 and PCT US85/01921.
There is no disclosure in the art of the use together of IL-2 and TNF in the treatment of bladder cancer. The present invention provides the art for the first time with the surprising technical effect that intravesically administered
IL-2 and TNF in combination can advantageously be used to treat bladder cancer.
The present invention relates more generally to the use in combination of interleukin-2 and tumour necrosis factor to treat bladder cancer, especially advanced transitional bladder carcinoma.
According to the present invention, therefore, there is provided the use of interleukin-2 and tumour necrosis factor in the manufacture of a medicament for the treatment of bladder cancer. Preferably, the medicament is an intravesical formulation. The IL-2 and TNF are preferably recombinant human
IL-2 and TNF (optionally in the form of muteins). The IL-2 and
TNF are preferably in synergistically effective amounts. Other aspects and embodiments of the invention are defined in the claims.
The invention includes products containing TNF and IL-2 as a combined preparation for simultaneous, separate and sequential use in the therapeutic or prophylactic treatment of bladder cancer by intravesical administration in human patients.
As used herein, the term "synergistically effective amount" as applied to IL-2 and TNF 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 TNF versus dose of IL-2 versus host survival, either the dose TNF axis or the IL-2 axis. The dose response curve used to determine synergy herein is more fully described by Sandle 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, cure is defined as cure of the host after 14 days from the date of tumor implantation into the host for Meth A tumors and after 60 days for all other tumors. 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 TNF. The highest survival rates on the dose response curve correlate with the optimum dosage levels.
As used herein, the term "recombinant" refers to TNF or IL-2 produced by recombinant DNA techniques wherein generally the gene coding for the TNF or IL-2 is cloned by known recombinant
DNA technology. For example, by using the human TNF or IL-2 cDNA as a template, the gene showing complementarity to the human TNF or IL-2 cDNA is inserted into a suitable DNA vector such as a bacterial plasmid, preferably 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, pCRl, pMB9 and pSC1. The transformed host may be eucaryotic or procaryotic, preferably a procaryotic host.
As used herein, the teritt "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 TNF and IL-2 are preferably administered simultaneously to the patient but may also be delivered sequentially.
Administration by intravesical instillation is preferred, in order to avoid possible side effects of systemic administration and to enable delivery of the active agents to the tumour site at a high concentration.
Simultaneous administration is preferably performed by instilling into the bladder through a catheter a solution containing the TNF and IL-2. Less preferably, separate solutions of TNF and IL-2 may be instilled at the same time into the bladder using a crossed section on the catheter.
In sequential administration, a solution of one of the active agents instilled after the other. Preferably, the second agent is instilled immediately after the first, in order to obtain substantially concomitant administration. Normally, in sequential administration the TNF is administered before the
IL-2, since administration in the reverse order is less effective.
The IL-2 and TNF will generally be formulated in a unit dosage intravesically instillable form (solution, suspension, emulsion), preferably in a pharmaceutically acceptable carrier medium which is inherently non-toxic and non-therapeutic.
Examples of such vehicles include saline, Ringer's solution, dextrose solution, mannitol and normal serum albumin. Nonaqueous 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.
Alternatively, the IL-2 and TNF may be made into a sterile, stable lyophilized formulation in which the purified IL-2 and
TNF are admixed with a water-soluble carrier such as mannitol, which provides bulk, and a sufficient amount of a surfactant such as sodium dodecyl sulfate to ensure the solubility of the recombinant IL-2 in water. The formulation is suitable for reconstitution in aqueous media for intravesical administration and it is stable and well-tolerated in human patients. The IL2 formulation method is more completely described in PCT
W085/04328.
In yet another alternative, the mixture of IL-2 and TNF may be administered in an adoptive immunotherapy method, together with isolated, lymphokine-activated lymphocytes in a pharmaceutically acceptable carrier, where the lymphocytes are reactive to tumor when administered with the TNF and IL-2 to humans suffering from the tumor. This method is described more fully in S. Rosenberg et al., New England Journal of Medicine (1985), 313:1485-1492. In another alternative, described in S.
Rosenberg et al., Science, 233:1313-1321 (1986), tumorinfiltrating lymphocytes (TIL) expanded in IL-2 may be adoptively transferred for the therapeutic treatment, particularly in combination with cyclophosphamide. The TIL approach of Rosenberg et al. may also be used herein.
An exemplary vehicle for the TNF and IL-2, whether administered in the same solution or separately, is phosphate buffered saline (PBS) (pH 7.4-7.8) containing human serum albumin, for example in an amount of from 0.05 to 0.3% w/v, preferably 0.1 to 0.25% w/v. In the case of adult human patients, a suitable total volume of fluid instilled at each administration is in the order of 50 ml (e.g. 25 ml of TNF solution followed by 25 ml of IL-2 solution), for example a total volume of from 40 to 60 ml.
For IL-2, lyophilized product can be reconstituted with a small quantity of water (e.g. 1 mg product per approximately 1.2 ml water), and thereafter diluted with either 5% dextrose or 5% dextrose in 0.25% human albumin.
Dilution can be in 100 to 250 ml of diluent.
The solution or solutions are appropriately instil led over a period of 1 to 2 hours. Patients may be instilled on a weekly basis or at other frequency in accordance with the discretion of the medical practitioner. At each instillation, patients preferably receive from 250 to 1,000 ssg, more preferably 400 to 900 ssg, TNF and from 105 to 108
IU, more preferably 0.5 to 75.106 IU, IL-2. Typically TNF is administered in an amount of from 500 to 800 Ug per instillation and IL-2 in an amount of from 0.6.106 to 60.106
IU. rIL-2 is normally supplied as a lyophilized powder stored under refrigeration whereas- TNF is normally supplied in a solution which must be stored at -20 C or colder.
Lyophilized rIL-2 is simply made up into a solution by mixing it with the requisite liquid carrier; the solutions are stable for up to 48 hours at room temperature. Frozen
TNF must be allowed to thaw at room temperature without heating or shaking. The thawed solution is stable at room temperature but proteinaceous particles may form if it is shaken, in which case the solution cannot be used. The thawed solution can be diluted as necessary.
When patients are instilled using a solution containing TNF and
IL-2 in combination, the combined solution may be prepared in situ (e.g. in a hospital pharmacy) by reconstitution of each component using, for example, PBS to prepare 25ml of reconstituted solution and then adding one reconstituted solution to the other, followed by gently swirling the combined solution.
The IL-2 and TNF may be any IL-2 and TNF prepared from tissue cultures or by recombinant techniques, and from any mammalian source, such as, e.g. mouse, rat, rabbit, primate, pig and human. Preferably the TNF is derived from rabbit or human sources, more preferably human and the IL-2 is derived from a human source. More preferably, the IL-2 and TNF are recombinant human IL-2 and recombinant human TNF. Desirably, the recombinant human IL-2 and TNF are unglycosylated. 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 native human IL-2 gene and expressing it in transformed microorganisms.It may also be an IL-2 mutein as described in US Patent No. 4,518,584, in which the cysteine normally occurring at position 125 of the wild-type or native molecule has been replaced by a neutral amino acid such as serine or alanine, or an IL-2 mutein in which the methionine normally occurring at position 104 of the wild-type or native molecule has been replaced by a neutral amino acid such as alanine.
Preferably, the IL-2 is an unglycosylated protein which is produced by a microorganism which has been transformed with the human cDNA sequence or a modified human cDNA 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 Taniguchi et el, Nature (1983), 302:305-310;
Devos, Nucleic Acids Research (1983),11:4307-4323; and by
European Patent Publication Nos. 91,539 and 88,195; and in US
Patent 4,518,584, supra, as well as IL-2alalO4serl25. Most preferably, the IL-2 is the des-alal-IL-2serl25 mutein in which the initial terminal alanine is deleted and the cysteine at position 125 is replaced by a serine residue. Any combination of up to 5 of the first 5 N-terminal amino acid residues of the
IL-2 may be deleted.
The IL-2 may be produced and purified to clinical purity by the method described and claimed in US Patent No. 4,569,790.
In an alternative formulation, the IL-2 may be solubilised, not by a detergent, but by reacting the IL-2 with an activated polymer selected from polyethylene glycol homopolymers and polyoxyethylated polyols such as polyoxyethylated glycerol.
The polymer preferably has a molecular weight of from 300 to 100,000 daltons, more preferably 350 to 40,000 daltons. The polymer is activated by conjugation with a coupling agent having terminal groups reactive with both the free amine or thiol groups of the IL-2 and the hydroxyl group of the polymer.
Examples of such coupling agents include hydroxynitrobenzene sulfonic ester, cyanuric acid chloride, and N-hydroxysuccinimide. This modification eliminates the necessity for adding detergents to solubilise the IL-2 at physiological pH.
The IL-2 is then formulated directly with the water-soluble carrier and buffer as described above, the formulation is lyophilised, and the lyophilised mixture may be reconstituted as described above.
The recombinant human TNF may be obtained as described by
Pennica et al, Nature (1984), 312:724-729; Yamada et al, J.
Biotechnology (1985), 3:141-153; Wang et al, Science (1985), 228:149-154; EP 155,549; EP 158,286; EP 168,214 and PCT US 85/01921. The TNF is preferably human unglycosylated TNF having a molecular weight of about 15,000 - 20,000 on SDS-PAGE.
The recombinant rabbit TNF may be obtained as described in EP 146,026 and EP 148,311. Preferably the TNF is a human TNF mutein wherein up to the first ten amino acid residues have been deleted, optionally using the procedures described in US 4677063/4, for example a mutein in which the first 4, 6, 7, 8 or 9 residues are - deleted, or the TNF is a cysteine-depleted mutein prepared analogously to that described in US Patent No.
4,518,584. The TNF may also be a mutein which is both an Nterminal deletion mutein and a cysteine-depleted mutein.
Example 1
Preparation of IL-2 and TNF Formulation (i) IL-2
The IL-2 selected for use is rIL-2 sold under the trade mark
PROLEUKIN by Cetus Corporation. PROLEUKIN is des-alanyl-1, serine-125 human interleukin-2 and differs from native IL-2 in the following ways: a) It is not glycosylated because it is derived from E.Coli.
b) The molecule has now no N-terminal alanine. The codon for this amino acid is deleted during the genetic engineering procedure.
c) The molecule has serine substituted for cysteine at amino acid position 125. This is accompanied by site specific mutation during the genetic engineering procedure.
The two amino acid changes result in a more homogenous IL-2 product. The modified molecule has similar properties of Tlymphocyte proliferation as human native IL-2.
The PROLEUKIN is supplied as a sterile, white, lyophilized powder in 5 ml stoppered vials. It is pyrogen-free with endotoxin levels less than 0.4 EU per mg rIL-2.
Following reconstitution, each single use vial delivers 1 ml solution containing 1 mg (18 x 106 IU) of human recombinant interleukin-2.
The biological potency of PROLEUKIN is determined by a lymphocytic proliferation bioassay and is expressed in
International Units (IU) as established in relationship to the first WHO International Standard. The nominal specific activity of PROLEUKIN is 18 x 106 6 IU/mg.
(ii) TNF
The TNF used in this example, has been purified to homogeneity, and meets the following specifications:
Test Specification a) USP sterility pass b) rabbit pyrogen pass c) general safety pass d) potency greater than 5 x 106 units/mg rTNF
Each vial contains 0.3 mg rTNF in 1.2 ml of solution. The rTNF concentration is 0.25 mg/ml. In addition to rTNF, the solution contains 1% mannitol in sodium phosphate buffer. There is no bacteriostatic agent. The pH of the solution is between 7.2 and 7.8.
Vials are shipped frozen (-20 o C.) on dry ice. Upon receipt, vials are inspected carefully and vials that have thawed during shipment are not used. The frozen liquid is stored -20 e C or colder.
Before use the vials are removed from the freezer and allowed to thaw at room temperature. A warm water bath or other technique to accelerate thawing is not used.
After thawing, the solution is stable at room temperature, but is used within 3 hours for sterility considerations. Thawed vials are not shaken since this may result in the formation of proteinaceous partIcles. Vials noted to contain such particles are not used.
(iii) Preparation of Formulation
One vial containing lmg of PROLEUKIN is reconstituted using
PBS (0.01 M phosphate, 0.15M NaCl; pH 7.4; 0.1% w/v human serum albumin; 18 x 106 IU) to prepare 75 ml reconstituted solution.
Two vials each containing a solution of 0.3mg rTNF (1% mannitol in sodium phosphate buffer) are carefully thawed without
shaking at room temperature. The thawed solutions are
reconstituted with PBS (0.01 M phosphate; 0.15 M NaCl; pH 7.4; 0.1t w/v human serum albumin) to prepare a single solution with
a total volume of 30 ml (600 pg TNF).
25ml of the reconstituted TNF (500 eg TNF) is added to 25 ml of
the IL-2 solution (6.106 IU IL-2) and gently swirled.
Example 2
Treatment Plan
All eligible patients who have at least one marker lesion left in the bladder are treated as described below.
Initially 3 patients are entered on study. Each patient receives single weekly 1-2 hour instillations of rIL-2 and rTNF into the bladder for 6 consecutive weeks. This constitutes one cycle of therapy.
The first 3 patients start at dose level 1 for a first cycle.
The total amounts of rIL-2 and rTNF to be instilled are diluted separately in 25 ml PBS (0.01 M phosphate, 0.15 M NaCl; pH=7.4) containing 0.25% Human Serum Albumin. Both solutions are instilled at the same time into the bladder using a crossed section on the catheter. The total volume instilled is then 50 ml. In one trial, the combined solution of Example 1 is instiled.
All patients receive 500 pug/50 ml rTNF per instillation. rIL-2 is given according to the following dose escalation schedule: 1 0,6.106IU/50ml 2 6.10 6 IU/50 ml 3 60.10 6 IU/50 ml
The first instillation of rIL-2 and rTNF is given 2 weeks after
TUR (transurethral resection) or after the disappearance of all side effects of previous treatment.
In absence of tumour progression or unacceptable toxicity, a second cycle of 6 week instillations is given, after 14 days of rest.
10-14 days after the end of the first and the second cycle of rIL-2 (6 and 14 weeks after treatment start respectively) patients are evaluated.
Claims (24)
1. The use of IL-2 and TNF in the manufacture of a medicament
for intravesical administration for the treatment of
bladder cancer.
2. A pharmaceutical or veterinary formulation comprising TNF
and IL-2, characterised in that the formulation is adapted
for only intravesical administration and comprises IL-2 and
TNF.
3. A method of manufacturing a pharmaceutical or veterinary
formulation for intravesical administration for the
treatment of bladder cancer, comprising formulating IL-2
and TNF for intravesical administration.
4. A method of preparing a formulation for use in intravesical
administration for the treatment of bladder cancer together
with TNF, comprising manufacturing a formulation containing
IL-2.
5. A method of preparing a formulation for use in intravesical
administration for the treatment of bladder cancer when
combined with TNF, comprising manufacturing a formulation
containing IL-2.
6. A method of preparing a formulation for use in intravesical
administration for the treatment of bladder cancer together
with IL-2, comprising manufacturing a formulation
containing TNF.
7. A method of preparing a formulation for use in intravesical
administration for the treatment of bladder cancer when
combined with IL-2, comprising manufacturing a formulation
containing TNF.
8. The use of Claim 1, a formulation as claimed in Claim 2 or
a method as claimed in any one of Claims 3 to 7, wherein
the IL-2 is rIL-2 and/or the TNF is rTNF.
9. The use of Claim 1 or Claim 8, a formulation as claimed in
Claim 2 or Claim 8 or a method as claimed in any one of
Claims 3 to 8, wherein the TNF is human or rabbit TNF
and/or IL-2 is human IL-2.
10. The use of Claim 9 or a formulation or a method as claimed
in Claim 9, wherein the TNF is a mutein with the first
eight amino acids deleted and/or the IL-2 is desala1-IL-2 ser125.
11. The use of any one of Claims 1 or 8 to 10, wherein the
medicament is in unit form and comprises from 250 to 1000 5 TNF and/or from 10 to 108 IU IL-2 and preferably from
400 to 900 jig TNF and/or from 0.5 x 106 to 75 x 10 6 IU IL
2.
12. A formulation as claimed in any one of Claims 2, 8 or 9 or
method as claimed in any one of Claims 3 to 10, wherein the
formulation is in unit form and the TNF and/or IL-2 is in
an amount as defined in Claim 11.
13. A method of treating bladder cancer, comprising the
simultaneous or sequential intravesical administration to a
human or animal suffering bladder cancer of IL-2 and TNF.
14. A method as claimed in Claim 13, wherein the IL-2 and TNF
are administered simultaneously.
15. A method as claimed in Claim 13 or Claim 14, wherein the
IL-2 and/or the TNF are of recombinant origin.
16. A method as claimed in Claim 15, wherein the TNF is a
mutein with the first eight amino acids deleted and/or the
IL-2 is desala1-IL-2 ser125.
17. A method as claimed in any one of Claims 13 to 16, wherein
the TNF is administered in an amount of from 250 to 1000 Fg, preferably 400 to 900 pg, and the IL-2 is an amount of
from 10 to+10 9 IU, preferably 0.5 to 75.1or IU.
18. IL-2 for use in intravesical instillation into the human or
animal bladder in simultaneous or sequential instillation
with TNF for the treatment of bladder cancer.
19. TNF for use in intravesical instillation into the human or
animal bladder in simultaneous or sequential instillation
with IL-2 for the treatment of bladder cancer.
20. A pharmaceutical or veterinary formulation comprising IL-2
and TNF and for intravesical instillation into the human or
animal bladder for the treatment of bladder cancer.
21. A pharmaceutical formulation in unit form comprising from
40 to 60 ml of a solution containing IL-2 and TNF and
acceptable for intravesical instillation into the human
bladder.
22. A formulation as claimed in Claim 21, wherein the IL-2
and/or TNF are as defined in any one of Claims 8 to 10 and/or are in amounts as defined in Claim 11.
23. Products containing TNF and IL-2 as a combined preparation
for simultaneous, separate or sequential use in the
therapeutic or prophylactic treatment of bladder cancer by
intravesical administration in human patients.
24. Products as claimed in Claim 23 and further defined by the
specific features of any one or more of Claims 8 to 11 or
21.
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GB9119500A GB2260902A (en) | 1991-09-12 | 1991-09-12 | Interleukin-2 and tumour necrosis factor for treating bladder cancer |
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GB9119500A GB2260902A (en) | 1991-09-12 | 1991-09-12 | Interleukin-2 and tumour necrosis factor for treating bladder cancer |
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GB2260902A true GB2260902A (en) | 1993-05-05 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001017480A2 (en) * | 1999-09-09 | 2001-03-15 | Androsolutions, Inc. | Methods and compositions for preventing and treating urinary tract disorders |
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EP0248516A1 (en) * | 1986-04-09 | 1987-12-09 | Cetus Corporation | Compositions and the use of interleukin-2 and/or interferon-beta and tumour necrosis factor for combination therapy or in providing medicaments or formulations |
US4863727A (en) * | 1986-04-09 | 1989-09-05 | Cetus Corporation | Combination therapy using interleukin-2 and tumor necrosis factor |
WO1991002078A1 (en) * | 1989-08-07 | 1991-02-21 | Peptide Technology Ltd | Tumour necrosis factor binding ligands |
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NO871107L (en) * | 1986-04-09 | 1987-10-12 | Cetus Corp | COMBINATION THERAPY USING INTERLEUKIN-2 AND / OR INTERFERON-B AND TUMOR NECROSIS FACTOR. |
EP0248516A1 (en) * | 1986-04-09 | 1987-12-09 | Cetus Corporation | Compositions and the use of interleukin-2 and/or interferon-beta and tumour necrosis factor for combination therapy or in providing medicaments or formulations |
US4863727A (en) * | 1986-04-09 | 1989-09-05 | Cetus Corporation | Combination therapy using interleukin-2 and tumor necrosis factor |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001017480A2 (en) * | 1999-09-09 | 2001-03-15 | Androsolutions, Inc. | Methods and compositions for preventing and treating urinary tract disorders |
WO2001017480A3 (en) * | 1999-09-09 | 2001-11-01 | Androsolutions Inc | Methods and compositions for preventing and treating urinary tract disorders |
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