CA2144648A1 - Restoration of immunocompetency to t helper cells in hiv infected patients - Google Patents
Restoration of immunocompetency to t helper cells in hiv infected patientsInfo
- Publication number
- CA2144648A1 CA2144648A1 CA002144648A CA2144648A CA2144648A1 CA 2144648 A1 CA2144648 A1 CA 2144648A1 CA 002144648 A CA002144648 A CA 002144648A CA 2144648 A CA2144648 A CA 2144648A CA 2144648 A1 CA2144648 A1 CA 2144648A1
- Authority
- CA
- Canada
- Prior art keywords
- antibodies
- antagonist
- helper cells
- interleukin
- antibody
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- 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
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- 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]
- A61K38/2066—IL-10
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/5428—IL-10
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Genetics & Genomics (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Microbiology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Mycology (AREA)
- Toxicology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pyrrole Compounds (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
This invention relates to the use of antagonists to IL-10 such as anti-lL-10 antibodies for pharmaceutical administration to patients infected with an immunodefenciency virus. The administration of these antibodies restores the ability of T helper cells to produce IL-2.
Description
~VO 94/06473 2 1 4 4 6 ~ 8 PCI/US93/08562 ltF~TORATION OF IMMUNOCO~I'~ CY TO T HFTRF~ F.T.T.!~ IN
~V T~FFCI FD PATIF.~TS
BACKGROIJND OF T~lF T~V~ION
Field of the invention.
This invention relates to the use of antagonists against IL-10 for pharmaceutical administration to patients infected with a immunodeficiency virus. The administration of these antagonists restores the ability of T helper cells to produce IL-2.
SUMMARY OF THE INVENTION
This invention provides methods of increasing the level of IL-2 produced by T helper cells in a patient infected with a human immunodeficiency virus. The method comprises administering an 20 amount of an antagonist of interleukin 10 wherein said amount is effective to inaease the patient's T helper cell production of IL-2. The antagonists are preferably administered intravenously. A preferred antagonist is an antibody specific for binding to IL-10. The antibodies can be chimeric, recombinant, polyclonal or monodonal. Autologous 25 antibodies, human or humanized antibodies are preferred for safety when human patients are being treated. The ~referred single dosage of antibodies is 1-10 mg/kg body weight per antibody. Alternatively the amount of the antibody adrninistered in a single dose is about 10 to about 100 ~lg per milliliter of patient sera.
D~TAII ED DESCRIPIION
This invention provides an effective means for increasing production of IL-2 in T helper cells when said levels are being inhibited 35 by excessive levels of IL-10 attendant an infection of lentiviruses known as the human immunodeficiency virus [HIV].
WO 94/06473 PCr/US93/o~
21446~8 2-This chronic and often fatal viral infection is typified by an imbalance in T helper cellular responses. The result of this imbalance is an inhibition of IL-2 production by nonvirally infected T helper cells due to excessive levels of IL-10. The IL-10 is produced by a number of 5 different cells including a subset of the T helper cells.
The maintenance of IL-2 production is beneficial to HIV infected patients. IL-2 is responsible for T cell proliferation and is a key indicator of the status of the immune system.
The reduction of IL-2 production can be halted by administration of adequate amounts of antagonists specific for IL-10. Antagonists of IL-10 can be made by mutating the amino acid sequence of IL-10 using standard mutagenesis methods. Such methods indude the use of M13 15 vectors to introduce single site mutations, to delete random amino acids from IL-10 or to add amino acids. The resulting muteins are then tested in standard assays for the ability to compete with nonrnutated IL-10.
Suitable assays are described below and indude in ~itro cell assays where IL-2 dependent proliferation is initiated by the presence of exogenous 20 IL-10. This strategy have been used to characterize the functional domains of numerous proteins such as thrombomodulin, human growth factor and tissue plasminogen activator.
Alternatively, the antagonist can be an antibody specific for 25 binding to IL-10 [a IL-10] and which illtefÇ~es with its binding to the T-helper receptor. a IL-10 is produced in a variety of conventional ways.
A general review of antibody production can be found in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Pubs., N.Y.
(1988) or in Colligan et al. Eds., 1991 and Suppl. Current Protocols in 30 Immunology, Green Wiley, NY, NY. Antibodies can be a polyclonal mixture or monoclonal. Antibodies can ~e intact immunoglobulins derived from natural sources or from recombinant sources. Antibodies also include the immunoreactive portions of intact immunoglobulins.
In brief, methods to obtain a IL-10 antibodies involve administering an amount of antigen sufficient to induce a humoral response in a maIrunal. The antibodies are either collected from the mammal's sera or lymphocytes removed, immortalized and those cell ~WO 94/06473 2 1 4 4 g 4 8 PCr/US93/08562 ~- 3-~ .. , clones secreting the desired antibodies isolated and cultured for harvest of the desired antibodies. Antibodies against IL-10 are described by Mosmann et al., 1990 J. Immunol. 145:2938.
These methods require adequate sources of IL-10 as antigens. The antigens can either be intact IL-10 or immunoreactive peptides.
Recombinant expression of IL-10 is a convenient means for obtaining IL-10 for use as antigns. For a general review of the applicable recombinant technology see Sambrook, ef al., Molecular Cloning - A
Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 1989. Specific techniques for expressing and purifying IL-10 are known. Expression of IL-10 is described in PCT/US/03554 (WO/91/00349) and in Malefyt, et al., 1992, Curr. Opin. Immunology, 4:314-320. Alternatively, peptide synthesis may be used to obtain intact 1 5 or immunoreactive portions of IL-10.
The antibodies for use in this invention are preferably autologous for the patient thereby minimizing further immunological problems.
Immunodeficient individuals will tend to be less reactive to non~elf antibodies, and thus non-self antibodies derived from cells of the same species are also useful. Antibodies of different species are useful but means to control possible adverse immunoreactions must be undertaken. For example, humanized rat antibodies can minimize immune responses in human patients.
The antibodies for use in this invention are typically neutralizing antibodies and will ~referably have binding constants which are greater than or approximates the affinity of IL-10 for its natural receptor.
Antibodies having a binding constant 100-fold less than these cytokines for their corresponding receptors are less preferred. Binding comparisons are carried out using standard equilibrium methods. The basic technology is described in Chapter 25 of Vol. 1: Immunochemistry, Ed. D.M. Weir, 4th Ed. 1986, Blackwell Scientific Publ. 25. 1-25.30.
Alternatively, one can use an assay for determining the molar excess of antibody which neutrali~es a defined amount of IL-10 in a standard in vitro bioassay. Examples of such assays are found in Mosmann and Fong, 1989, J. Immunol. Methods, 116: 151 (IL-4) and Fiorentino et al., WO 94/06473 PCr/US93/0~
214~648 1989, J. Exp. Med. 170: 2081. A reasonable range are those antibodies which neutralize a given amount of IL-10 in a 10 to 1,000 fold excess.
The means of administration of the antagonists, e.g. a IL-10 are 5 typically parenteral, preferably intravenous. The antagonists are infused into the patient using standard intravenous techniques. The antagonists are first suspended into a sterile, physiologically-compatible media, such as phosphate buffered saline. Pharrnaceutically acceptable excipients such as lecithin, glucose, dextrose, antibiotics may also be 10 included with the antagonists.
When the antagonists are antibodies, they are administered in an arnount which provides circulating levels of IL-10 at about 1 to 150 ~g/ml and preferably 10 to 100 ~Lg/ml of sera for each antibody. The 15 antibodies have a 2-7 day half-life and repeated administration is necessary when levels of IL-10 are below these levels. Total amount of oc IL-10 applied per administration are between 1 and 10 mg/kg of body weight for each antibody.
The method will increase IL-2 production and it is preferred that said levels approach or exceed 100% of normal. Increases of greater than 50% of the IL-2 production before treatment are considered good.
Treatment can be terminated when the T helper cells are producing levels of IL-2 at 10 to 100% of normal when measured by any number of conventional assays.
These conventional assays fall into two categories. The first category are bioassays that measure IL-2 dependent proliferation of any of several immortal cell lines which proliferate in the presence of IL-2.
An example of such a cell line is CTLL. Cell division is measured by radiolabelled thymidine uptake. The second category are functional assays and involve the use of immunoassays directly measuring IL-2 such as ELISA. A general overview of this art can be found in Mosmann and Fong, 1989, Specific assays for cytokine production by T
cells, J. Immunol. Meth. 1 1 6: 151-158.
Conventional antiviral therapies such as AZT, may also be used in conjunction with this invention.
~CT/U593/o8s~
~WO 94/06473 . ~ ~-Although the present invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be recognized that certain changes and 5 modifications may be practiced within the scope of the claims.
~V T~FFCI FD PATIF.~TS
BACKGROIJND OF T~lF T~V~ION
Field of the invention.
This invention relates to the use of antagonists against IL-10 for pharmaceutical administration to patients infected with a immunodeficiency virus. The administration of these antagonists restores the ability of T helper cells to produce IL-2.
SUMMARY OF THE INVENTION
This invention provides methods of increasing the level of IL-2 produced by T helper cells in a patient infected with a human immunodeficiency virus. The method comprises administering an 20 amount of an antagonist of interleukin 10 wherein said amount is effective to inaease the patient's T helper cell production of IL-2. The antagonists are preferably administered intravenously. A preferred antagonist is an antibody specific for binding to IL-10. The antibodies can be chimeric, recombinant, polyclonal or monodonal. Autologous 25 antibodies, human or humanized antibodies are preferred for safety when human patients are being treated. The ~referred single dosage of antibodies is 1-10 mg/kg body weight per antibody. Alternatively the amount of the antibody adrninistered in a single dose is about 10 to about 100 ~lg per milliliter of patient sera.
D~TAII ED DESCRIPIION
This invention provides an effective means for increasing production of IL-2 in T helper cells when said levels are being inhibited 35 by excessive levels of IL-10 attendant an infection of lentiviruses known as the human immunodeficiency virus [HIV].
WO 94/06473 PCr/US93/o~
21446~8 2-This chronic and often fatal viral infection is typified by an imbalance in T helper cellular responses. The result of this imbalance is an inhibition of IL-2 production by nonvirally infected T helper cells due to excessive levels of IL-10. The IL-10 is produced by a number of 5 different cells including a subset of the T helper cells.
The maintenance of IL-2 production is beneficial to HIV infected patients. IL-2 is responsible for T cell proliferation and is a key indicator of the status of the immune system.
The reduction of IL-2 production can be halted by administration of adequate amounts of antagonists specific for IL-10. Antagonists of IL-10 can be made by mutating the amino acid sequence of IL-10 using standard mutagenesis methods. Such methods indude the use of M13 15 vectors to introduce single site mutations, to delete random amino acids from IL-10 or to add amino acids. The resulting muteins are then tested in standard assays for the ability to compete with nonrnutated IL-10.
Suitable assays are described below and indude in ~itro cell assays where IL-2 dependent proliferation is initiated by the presence of exogenous 20 IL-10. This strategy have been used to characterize the functional domains of numerous proteins such as thrombomodulin, human growth factor and tissue plasminogen activator.
Alternatively, the antagonist can be an antibody specific for 25 binding to IL-10 [a IL-10] and which illtefÇ~es with its binding to the T-helper receptor. a IL-10 is produced in a variety of conventional ways.
A general review of antibody production can be found in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Pubs., N.Y.
(1988) or in Colligan et al. Eds., 1991 and Suppl. Current Protocols in 30 Immunology, Green Wiley, NY, NY. Antibodies can be a polyclonal mixture or monoclonal. Antibodies can ~e intact immunoglobulins derived from natural sources or from recombinant sources. Antibodies also include the immunoreactive portions of intact immunoglobulins.
In brief, methods to obtain a IL-10 antibodies involve administering an amount of antigen sufficient to induce a humoral response in a maIrunal. The antibodies are either collected from the mammal's sera or lymphocytes removed, immortalized and those cell ~WO 94/06473 2 1 4 4 g 4 8 PCr/US93/08562 ~- 3-~ .. , clones secreting the desired antibodies isolated and cultured for harvest of the desired antibodies. Antibodies against IL-10 are described by Mosmann et al., 1990 J. Immunol. 145:2938.
These methods require adequate sources of IL-10 as antigens. The antigens can either be intact IL-10 or immunoreactive peptides.
Recombinant expression of IL-10 is a convenient means for obtaining IL-10 for use as antigns. For a general review of the applicable recombinant technology see Sambrook, ef al., Molecular Cloning - A
Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 1989. Specific techniques for expressing and purifying IL-10 are known. Expression of IL-10 is described in PCT/US/03554 (WO/91/00349) and in Malefyt, et al., 1992, Curr. Opin. Immunology, 4:314-320. Alternatively, peptide synthesis may be used to obtain intact 1 5 or immunoreactive portions of IL-10.
The antibodies for use in this invention are preferably autologous for the patient thereby minimizing further immunological problems.
Immunodeficient individuals will tend to be less reactive to non~elf antibodies, and thus non-self antibodies derived from cells of the same species are also useful. Antibodies of different species are useful but means to control possible adverse immunoreactions must be undertaken. For example, humanized rat antibodies can minimize immune responses in human patients.
The antibodies for use in this invention are typically neutralizing antibodies and will ~referably have binding constants which are greater than or approximates the affinity of IL-10 for its natural receptor.
Antibodies having a binding constant 100-fold less than these cytokines for their corresponding receptors are less preferred. Binding comparisons are carried out using standard equilibrium methods. The basic technology is described in Chapter 25 of Vol. 1: Immunochemistry, Ed. D.M. Weir, 4th Ed. 1986, Blackwell Scientific Publ. 25. 1-25.30.
Alternatively, one can use an assay for determining the molar excess of antibody which neutrali~es a defined amount of IL-10 in a standard in vitro bioassay. Examples of such assays are found in Mosmann and Fong, 1989, J. Immunol. Methods, 116: 151 (IL-4) and Fiorentino et al., WO 94/06473 PCr/US93/0~
214~648 1989, J. Exp. Med. 170: 2081. A reasonable range are those antibodies which neutralize a given amount of IL-10 in a 10 to 1,000 fold excess.
The means of administration of the antagonists, e.g. a IL-10 are 5 typically parenteral, preferably intravenous. The antagonists are infused into the patient using standard intravenous techniques. The antagonists are first suspended into a sterile, physiologically-compatible media, such as phosphate buffered saline. Pharrnaceutically acceptable excipients such as lecithin, glucose, dextrose, antibiotics may also be 10 included with the antagonists.
When the antagonists are antibodies, they are administered in an arnount which provides circulating levels of IL-10 at about 1 to 150 ~g/ml and preferably 10 to 100 ~Lg/ml of sera for each antibody. The 15 antibodies have a 2-7 day half-life and repeated administration is necessary when levels of IL-10 are below these levels. Total amount of oc IL-10 applied per administration are between 1 and 10 mg/kg of body weight for each antibody.
The method will increase IL-2 production and it is preferred that said levels approach or exceed 100% of normal. Increases of greater than 50% of the IL-2 production before treatment are considered good.
Treatment can be terminated when the T helper cells are producing levels of IL-2 at 10 to 100% of normal when measured by any number of conventional assays.
These conventional assays fall into two categories. The first category are bioassays that measure IL-2 dependent proliferation of any of several immortal cell lines which proliferate in the presence of IL-2.
An example of such a cell line is CTLL. Cell division is measured by radiolabelled thymidine uptake. The second category are functional assays and involve the use of immunoassays directly measuring IL-2 such as ELISA. A general overview of this art can be found in Mosmann and Fong, 1989, Specific assays for cytokine production by T
cells, J. Immunol. Meth. 1 1 6: 151-158.
Conventional antiviral therapies such as AZT, may also be used in conjunction with this invention.
~CT/U593/o8s~
~WO 94/06473 . ~ ~-Although the present invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be recognized that certain changes and 5 modifications may be practiced within the scope of the claims.
Claims (8)
1. A method of increasing the level of T helper cell production of interleukin 2 in a patient infected with a human immunodeficiency virus said method comprising administering an amount of an antagonist of interleukin 10 (IL-10) effective to increase the patient's T
helper cell production of IL-2.
helper cell production of IL-2.
2. A method for the manufacture of a pharrnaceutical composition for increasing the level of T helper cell production of interleukin 2 in a patient infected with a human immunodeficiency virus comprising admixing an antagonist to IL-10 with a pharmaceutically acceptable carrier.
3. The method of any one of claims 1-2 in which the antagonist is an antibody to IL-10.
4. A pharmaceutical composition for increasing the level of T
helper cell production of interleukin 2 in a patient infected with a human immunodeficiency virus comprising an antagonist to IL-10 and a pharmaceutically acceptable carrier.
helper cell production of interleukin 2 in a patient infected with a human immunodeficiency virus comprising an antagonist to IL-10 and a pharmaceutically acceptable carrier.
5. The pharmaceutical composition of claim 4 in which the antagonist is an antibody to IL-10.
6. The use of an antagonist to IL-10 for increasing the level of T
helper cell production of interleukin 2 in a patient infected with a human immunodeficiency virus.
helper cell production of interleukin 2 in a patient infected with a human immunodeficiency virus.
7. The use of an antagonist to IL-10 for the manufacture of a medicament for increasing the level of T helper cell production of interleukin 2 in a patient infected with a human immunodeficiency virus.
8. The use of either claim 6 or 7 in which the antagonist to IL-10 is an antibody to IL-10.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US94731692A | 1992-09-18 | 1992-09-18 | |
| US07/947,316 | 1992-09-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2144648A1 true CA2144648A1 (en) | 1994-03-31 |
Family
ID=25485948
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002144648A Abandoned CA2144648A1 (en) | 1992-09-18 | 1993-09-16 | Restoration of immunocompetency to t helper cells in hiv infected patients |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0667789A1 (en) |
| JP (1) | JPH08501549A (en) |
| AU (1) | AU4856793A (en) |
| CA (1) | CA2144648A1 (en) |
| MX (1) | MX9305713A (en) |
| WO (1) | WO1994006473A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19529026C2 (en) * | 1995-07-28 | 1997-06-19 | Robert Sabat | Monoclonal antibodies against human interleukin-10 |
| AU6887096A (en) * | 1996-09-11 | 1998-04-02 | Patrick T. Prendergast | Immune direction therapy |
| DE19939653A1 (en) * | 1999-08-13 | 2001-02-22 | Thomas Huenig | Use of CD28 specific monoclonal antibodies for the production of a pharmaceutical composition |
| MXPA03002278A (en) | 2000-09-14 | 2004-12-03 | Beth Israel Hospital | Modulation of il-2- and il-15-mediated t cell responses. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL94878A (en) * | 1989-06-28 | 2003-01-12 | Schering Corp | Cytokine synthesis inhibitory factor, antagonists thereof and methods of using same |
| ES2138976T3 (en) * | 1991-08-06 | 2000-02-01 | Schering Corp | USE OF INTERLEUKIN-10 ANALOGS OR ANTAGONISTS TO TREAT ENDOTOXIN OR SUPERANTIGEN INDUCED TOXICITY. |
-
1993
- 1993-09-16 EP EP93921492A patent/EP0667789A1/en not_active Withdrawn
- 1993-09-16 JP JP6508193A patent/JPH08501549A/en active Pending
- 1993-09-16 WO PCT/US1993/008562 patent/WO1994006473A1/en not_active Application Discontinuation
- 1993-09-16 AU AU48567/93A patent/AU4856793A/en not_active Abandoned
- 1993-09-16 CA CA002144648A patent/CA2144648A1/en not_active Abandoned
- 1993-09-17 MX MX9305713A patent/MX9305713A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MX9305713A (en) | 1994-05-31 |
| JPH08501549A (en) | 1996-02-20 |
| AU4856793A (en) | 1994-04-12 |
| WO1994006473A1 (en) | 1994-03-31 |
| EP0667789A1 (en) | 1995-08-23 |
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