CA2188871C - Method for treating psoriasis - Google Patents
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- CA2188871C CA2188871C CA002188871A CA2188871A CA2188871C CA 2188871 C CA2188871 C CA 2188871C CA 002188871 A CA002188871 A CA 002188871A CA 2188871 A CA2188871 A CA 2188871A CA 2188871 C CA2188871 C CA 2188871C
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- interleukin
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- psoriasis
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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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- Pharmacology & Pharmacy (AREA)
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- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides a therapeutic method of treating a human subject for psoriasis which comprises administering to the subject an effective psoriatic dermatosis-inhibiting amount of IL-2 and a pharmaceutically acceptable carrier.
Description
WO 95/08340 PC'T/US93/08953 .d_ 2~ 8887 ~ ;
Psoriasis is a common chronic and recurrent disease characterized by hyperproliferation of the basal layer of the epidermis resulting in dry, well-circumscribed, silvery-scaled maculopapules and plaques of various sizes. The lesions occur predominantly on the elbows, knees, scalp, and trunk and microscopically show. characteristic parakeratosis and elongation of rete ridges. General health is rarely affected, although psoriatic arthritis, a destructive form of arthritis in the fingers and toes which often closely resembles rheumatoid arthritis, may develop in some patients.
Onset of psoriasis is usually gradual, however factors precipitating psoriatic eruptions include local trauma and occasionally severe sunburn, irritation, topical medications, chloroquine antimalarial therapy and withdrawal of systemic corticosteroids.
Although the cause of psoriasis is unknown, the following evidence implies that abnormalities in the cellular immune function exist:
1. depressed reactivity to contact allergen;
Psoriasis is a common chronic and recurrent disease characterized by hyperproliferation of the basal layer of the epidermis resulting in dry, well-circumscribed, silvery-scaled maculopapules and plaques of various sizes. The lesions occur predominantly on the elbows, knees, scalp, and trunk and microscopically show. characteristic parakeratosis and elongation of rete ridges. General health is rarely affected, although psoriatic arthritis, a destructive form of arthritis in the fingers and toes which often closely resembles rheumatoid arthritis, may develop in some patients.
Onset of psoriasis is usually gradual, however factors precipitating psoriatic eruptions include local trauma and occasionally severe sunburn, irritation, topical medications, chloroquine antimalarial therapy and withdrawal of systemic corticosteroids.
Although the cause of psoriasis is unknown, the following evidence implies that abnormalities in the cellular immune function exist:
1. depressed reactivity to contact allergen;
2. decreased delayed reactivity to interdermal challenge with antigen;
3. depressed response to major histocompatibility antigens;
4. depressed response to mitogens;
4 ~.n WO 95108340 2 ~ 3 8 ~ 7 ~ PCT/US93/08953 5. depressed lymphokine production to antigen challenge;
4 ~.n WO 95108340 2 ~ 3 8 ~ 7 ~ PCT/US93/08953 5. depressed lymphokine production to antigen challenge;
6. normal and decreased numbers of T-lymphocytes; and 7. decreased to normal suppressor T-lymphoctye function.
No current therapeutic methods exist which assure a cure of psoriasis. The simplest forms of treatment include topical applications of lubricants, keratolytics, and topical corticosteroids. Furthermore, a new treatment utilizing psoralens and high intensity ultraviolet A (PUVA) involves the oral administration of methoxsalen (average dose 40 mg) followed by exposure of the skin to long-wave ultraviolet light (330 to 360 nm).
Although this treatment may produce remissions for several months, repeated treatments with intensive light may cause skin cancer. Finally the most effective treatment in severe disabling psoriasis that is unresponsive to topical agents or PUVA involves oral administration of methotrexate.
Interleukin-2 (IL-2) is a lymphokine, produced predominantly by helper T-cells, which modulates the activation and proliferation of cytotoxic T-cells, natural killer (NK) cells, B cells, lymphokine-activated killer (LAK) cells, and possibly T suppressor cells.
Human IL-2 has been purified and its molecular structure has been determined. It is composed of a single polypeptide chain of 133 amino acid residues with a molecular weight of approximately 15,000 daltons which may be variably glycosylated without loss of biological activity. IL-2 and analogs thereof have been produced using recombinant DNA technology. For example, recombinant methionyl human interleukin-2 alanine-125 [r-met Hu IL-2 (ala-125)] is a non-glycosylated analog of natural human IL-2 which retains the full biological activity of recombinant natural sequence human IL-2 and is stable in vitro for at least six months. R-met Hu IL-2 (ala-125) differs from naturally-occurring human IL-2 by having an additional methionyl residue at position 1 and having the cysteine at position 125 substituted with an alanine residue. Its amino acid sequence, as well as methods for its production and purification, are disclosed in European patent publication number 136,489.
In clinical studies of recombinant IL-2 perfo-rmed to date, toxicity has been dose related and has consisted mainly of fever, chills, rigors, malaise, diarrhea, fluid retention, nausea, vomiting, and arthralgias. Additionally, increased serum creatinine and transaminases, anemia, eosinophilia, leukocytosis, rash, stomatitis, hypotension, joint pain, and mental confusion have been reported.
Gaspari, et. al., JAMA, ~: 1624-1629 (1987) reported the cutaneous effects which occurred in ten patients undergoing immunotherapy with IL-2 and autologous lymphokine-activated killer (LAK) cells, i.e., a subset of lymphoid cells activated with IL-2 which can mediated the regression of pulmonary and hepatic metastases originating from a variety of tumor cell lines, to treat cancer. Among their observations, Gaspari, et al. reported that pharmacologic doses of IL-2 exacerbated erythrodermic flare of psoriasis in two patient who presented with psoriasis.
One object of the present invention is to provide therapeutic methods of treating a subject for psoriasis.
SLmmarSr of t_h_e Invention 1:-The present invention provides a therapeutic method of treating a human subject for psoriasis. This method comprises administering to the subject an effective psoriatic dermatosis-inhibiting amount of IL-2 and a pharmaceutically acceptable carrier.
Provided herein are therapeutic methods of treating a human subject for psoriasis. The therapeutic methods provided herein comprise administering to the subject an effective psoriatic dermatosis-inhibiting amount of IL-2 and a pharmaceutically acceptable carrier. Within this application "psoriatic dermatosis inhibiting" means inducing complete or partial regression or preventing recurrence of psoriasis.
Additionally, within this application "interleukin-2"
and "IL-2" each means a polypeptide with an amino acid sequence, at least a portion of which is present in the amirio acid sequence of naturally-occurring human IL-2, said polypeptide being capable of modulating the activation and proliferation of human lymphocytes.
Examples of such polypeptides are naturally-occurring human IL-2 and recombinant IL-2s such as the IL-2s disclosed in U.S. Patent No. 4,738,927, the muteins disclosed in U.S. Patent Nos. 4,518,584, 4,530,787 and 4, 569, 790, e.g., r IL-2 ser 125', and r-met Hu IL-2 (ala-125). In a preferred embodiment of the invention, the IL-2 is r-met Hu IL-2 (ala-125) or r IL-2 ser 125 In one embodiment of the invention the IL-2 is administered to the subject parenterally, e.g., intravenously, intradermally, intramuscularly or subcutaneously, in which case the pharmaceutically .y WO 95/08340 ~ ? ~ ~ 7 ~ PCT/US93/08953 acceptable carrier preferably comprises an isotonic buffer, e.g., a sodium acetate/glucose buffer. The intravenous administration of the IL-2 may be by infusion or preferably by bolus injection.
Generally, the dosage of IL-2 administration will vary depending on considerations such as age, general health, sex, degree of psoriatic eruptions and/or lesions, contraindications, if any, and other variables. Dosage may vary from at least 1,000 units IL-2/kilogram of body weight to about 40,000 units IL-2/kilogram of body weight, preferably about 10,000 units/kilogram to about 20,000 units/kilogram of body weight. Units (U) of IL-2 activity of a sample are determined by the following bioassay: CTLL cells are plated in wells of plastic tissue culture dishes in the absence of IL-2. At time = 0, IL-2 samples (serially diluted) or IL-2 standards are added to the wells.
After twenty hours incubation, tritiated thymidine is added and the cultures incubated for an additional four hours. Cells are then harvested, washed, disrupted, and -their DNA collected on filters which are transferred to scintillation vials for radioactivity determination.
The amount of radioactive thymidine incorporated into cellular DNA is proportional to the amount of IL-2 present in the sample. Units of activity of a sample are determined by comparing the dilution at which 50$
maximal thymidine incorporation occurs with the dilution of standard causing 50~ maximal thymidine incorporation.
Therapeutic regimens sufficient to effect complete or partial regression or prevent recurrence of psoriasis will also vary depending on such considerations as mentioned above regarding IL-2 dosage, and will be readily ascertainable by those skilled in the art without undue experimentation. Depending on such considerations, the IL-2 may be administered daily, e.g. o.d., b.i.d or t.i.d.,or continuously, e.g., by pCTIUS93108953 intravenous infusion or via a transdermal patch.
Preferably the IL-2 is administered to the subject for at least two days. In one embodiment of the invention the IL-2 is administered for about four days. In another embodiment of the invention the IL-2 is administered for about ten days.
The following examples are provided by way of illustration and in no way limit the scope of the subject invention, which is defined by the claims appended hereto.
The final dosage form of r-met-Hu IL-2 (ala-125) for I.V. bolus injection included the following ingredients and their amounts diluted in either 1.1 ml or 5.3 ml H20:
r-met-Hu-IL-2 (ala-125) 0.45 t 0.30 mg/ml sodium acetate 10 ~ 5 mM
(buffer component) glucose 4.9 ~ 0.7~
Patient 001, who presented with psoriatic dermatosis, received I.V. bolus injections of either of the above-mentioned dosage forms of r-met-Hu IL-2 (ala-125) as follows:
Day 1 10,000 U/kg -Day 2 20,000 U/kg -Day 3 20,000 U/kg -Day 4 Dose withheld -Day 5 10,000 U/kg -~~ggg ~~ ; 2188871 On Day 8 the patient presented with exfoliative dermatitis and concurrent chills, fever, edema, total body rash and decreased range of motion in the extremities. r-met-Hu IL-2 (ala-125) therapy was discontinued until the patient recovered from the side effects. r-met-Hu IL-2 (ala-125) therapy was restarted on Day 15 and continued for five consecutive days at a dose of 2,500 U/kg.
Results On Day 9 the patient began to show recovery from the exfoliative dermatitis as well as the psoriatic dermatosis. By the time r-met-Hu-IL-2 (ala-125) therapy was restarted on Day 15, the patient presented with neither the side effects of therapy nor psoriatic dermatosis. Additionally, the patient's psoriatic condition did not recur for approximately one month after therapy was initiated. Approximately one month after therapy was initiated the patient presented with a minor relapse of psoriatic dermatitis.
No current therapeutic methods exist which assure a cure of psoriasis. The simplest forms of treatment include topical applications of lubricants, keratolytics, and topical corticosteroids. Furthermore, a new treatment utilizing psoralens and high intensity ultraviolet A (PUVA) involves the oral administration of methoxsalen (average dose 40 mg) followed by exposure of the skin to long-wave ultraviolet light (330 to 360 nm).
Although this treatment may produce remissions for several months, repeated treatments with intensive light may cause skin cancer. Finally the most effective treatment in severe disabling psoriasis that is unresponsive to topical agents or PUVA involves oral administration of methotrexate.
Interleukin-2 (IL-2) is a lymphokine, produced predominantly by helper T-cells, which modulates the activation and proliferation of cytotoxic T-cells, natural killer (NK) cells, B cells, lymphokine-activated killer (LAK) cells, and possibly T suppressor cells.
Human IL-2 has been purified and its molecular structure has been determined. It is composed of a single polypeptide chain of 133 amino acid residues with a molecular weight of approximately 15,000 daltons which may be variably glycosylated without loss of biological activity. IL-2 and analogs thereof have been produced using recombinant DNA technology. For example, recombinant methionyl human interleukin-2 alanine-125 [r-met Hu IL-2 (ala-125)] is a non-glycosylated analog of natural human IL-2 which retains the full biological activity of recombinant natural sequence human IL-2 and is stable in vitro for at least six months. R-met Hu IL-2 (ala-125) differs from naturally-occurring human IL-2 by having an additional methionyl residue at position 1 and having the cysteine at position 125 substituted with an alanine residue. Its amino acid sequence, as well as methods for its production and purification, are disclosed in European patent publication number 136,489.
In clinical studies of recombinant IL-2 perfo-rmed to date, toxicity has been dose related and has consisted mainly of fever, chills, rigors, malaise, diarrhea, fluid retention, nausea, vomiting, and arthralgias. Additionally, increased serum creatinine and transaminases, anemia, eosinophilia, leukocytosis, rash, stomatitis, hypotension, joint pain, and mental confusion have been reported.
Gaspari, et. al., JAMA, ~: 1624-1629 (1987) reported the cutaneous effects which occurred in ten patients undergoing immunotherapy with IL-2 and autologous lymphokine-activated killer (LAK) cells, i.e., a subset of lymphoid cells activated with IL-2 which can mediated the regression of pulmonary and hepatic metastases originating from a variety of tumor cell lines, to treat cancer. Among their observations, Gaspari, et al. reported that pharmacologic doses of IL-2 exacerbated erythrodermic flare of psoriasis in two patient who presented with psoriasis.
One object of the present invention is to provide therapeutic methods of treating a subject for psoriasis.
SLmmarSr of t_h_e Invention 1:-The present invention provides a therapeutic method of treating a human subject for psoriasis. This method comprises administering to the subject an effective psoriatic dermatosis-inhibiting amount of IL-2 and a pharmaceutically acceptable carrier.
Provided herein are therapeutic methods of treating a human subject for psoriasis. The therapeutic methods provided herein comprise administering to the subject an effective psoriatic dermatosis-inhibiting amount of IL-2 and a pharmaceutically acceptable carrier. Within this application "psoriatic dermatosis inhibiting" means inducing complete or partial regression or preventing recurrence of psoriasis.
Additionally, within this application "interleukin-2"
and "IL-2" each means a polypeptide with an amino acid sequence, at least a portion of which is present in the amirio acid sequence of naturally-occurring human IL-2, said polypeptide being capable of modulating the activation and proliferation of human lymphocytes.
Examples of such polypeptides are naturally-occurring human IL-2 and recombinant IL-2s such as the IL-2s disclosed in U.S. Patent No. 4,738,927, the muteins disclosed in U.S. Patent Nos. 4,518,584, 4,530,787 and 4, 569, 790, e.g., r IL-2 ser 125', and r-met Hu IL-2 (ala-125). In a preferred embodiment of the invention, the IL-2 is r-met Hu IL-2 (ala-125) or r IL-2 ser 125 In one embodiment of the invention the IL-2 is administered to the subject parenterally, e.g., intravenously, intradermally, intramuscularly or subcutaneously, in which case the pharmaceutically .y WO 95/08340 ~ ? ~ ~ 7 ~ PCT/US93/08953 acceptable carrier preferably comprises an isotonic buffer, e.g., a sodium acetate/glucose buffer. The intravenous administration of the IL-2 may be by infusion or preferably by bolus injection.
Generally, the dosage of IL-2 administration will vary depending on considerations such as age, general health, sex, degree of psoriatic eruptions and/or lesions, contraindications, if any, and other variables. Dosage may vary from at least 1,000 units IL-2/kilogram of body weight to about 40,000 units IL-2/kilogram of body weight, preferably about 10,000 units/kilogram to about 20,000 units/kilogram of body weight. Units (U) of IL-2 activity of a sample are determined by the following bioassay: CTLL cells are plated in wells of plastic tissue culture dishes in the absence of IL-2. At time = 0, IL-2 samples (serially diluted) or IL-2 standards are added to the wells.
After twenty hours incubation, tritiated thymidine is added and the cultures incubated for an additional four hours. Cells are then harvested, washed, disrupted, and -their DNA collected on filters which are transferred to scintillation vials for radioactivity determination.
The amount of radioactive thymidine incorporated into cellular DNA is proportional to the amount of IL-2 present in the sample. Units of activity of a sample are determined by comparing the dilution at which 50$
maximal thymidine incorporation occurs with the dilution of standard causing 50~ maximal thymidine incorporation.
Therapeutic regimens sufficient to effect complete or partial regression or prevent recurrence of psoriasis will also vary depending on such considerations as mentioned above regarding IL-2 dosage, and will be readily ascertainable by those skilled in the art without undue experimentation. Depending on such considerations, the IL-2 may be administered daily, e.g. o.d., b.i.d or t.i.d.,or continuously, e.g., by pCTIUS93108953 intravenous infusion or via a transdermal patch.
Preferably the IL-2 is administered to the subject for at least two days. In one embodiment of the invention the IL-2 is administered for about four days. In another embodiment of the invention the IL-2 is administered for about ten days.
The following examples are provided by way of illustration and in no way limit the scope of the subject invention, which is defined by the claims appended hereto.
The final dosage form of r-met-Hu IL-2 (ala-125) for I.V. bolus injection included the following ingredients and their amounts diluted in either 1.1 ml or 5.3 ml H20:
r-met-Hu-IL-2 (ala-125) 0.45 t 0.30 mg/ml sodium acetate 10 ~ 5 mM
(buffer component) glucose 4.9 ~ 0.7~
Patient 001, who presented with psoriatic dermatosis, received I.V. bolus injections of either of the above-mentioned dosage forms of r-met-Hu IL-2 (ala-125) as follows:
Day 1 10,000 U/kg -Day 2 20,000 U/kg -Day 3 20,000 U/kg -Day 4 Dose withheld -Day 5 10,000 U/kg -~~ggg ~~ ; 2188871 On Day 8 the patient presented with exfoliative dermatitis and concurrent chills, fever, edema, total body rash and decreased range of motion in the extremities. r-met-Hu IL-2 (ala-125) therapy was discontinued until the patient recovered from the side effects. r-met-Hu IL-2 (ala-125) therapy was restarted on Day 15 and continued for five consecutive days at a dose of 2,500 U/kg.
Results On Day 9 the patient began to show recovery from the exfoliative dermatitis as well as the psoriatic dermatosis. By the time r-met-Hu-IL-2 (ala-125) therapy was restarted on Day 15, the patient presented with neither the side effects of therapy nor psoriatic dermatosis. Additionally, the patient's psoriatic condition did not recur for approximately one month after therapy was initiated. Approximately one month after therapy was initiated the patient presented with a minor relapse of psoriatic dermatitis.
Claims (18)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A use of a pharmaceutical composition comprising an amount of interleukin-2 from at least 1,000 units to about 40,000 units per kilogram of body weight sufficient to cause at least partial regression of a pre-existing condition of psoriasis and a pharmaceutically acceptable carrier, for treating a human subject for a pre-existing condition of psoriasis.
2. A use of a pharmaceutical composition comprising an amount of interleukin-2 from at least 1,000 units to about 40,000 units per kilogram of body weight sufficient to cause at least partial regression of a pre-existing condition of psoriasis and a pharmaceutically acceptable carrier, for the production of a medicament for treating a human subject for a pre-existing condition of psoriasis.
3. The use according to claim 1 or 2, wherein the interleukin-2 is used parenterally.
4. A use according to claim 3, wherein the pharmaceutical acceptable carrier comprises an isotonic buffer.
5. A use according to claim 3, wherein the interleukin-2 is used intravenously.
6. A use according to claim 5, wherein the interleukin-2 is used by bolus injection.
7. A use according to claim 5, wherein the interleukin-2 is used by infusion.
8. A use according to claim 1 or 2, wherein the interleukin-2 comprises recombinant methionyl human interleukin-2 alanine-125.
9. A use according to claim 1 or 2, wherein the interleukin-2 comprises recombinant human interleukin-2 serine-125.
10. A use according to claim 1 or 2, wherein the composition is used according to a therapeutic regimen sufficient to effect complete or partial regression or prevent recurrence of psoriasis.
11. A use according to claim 10, wherein the therapeutic regimen comprises the use of the interleukin-2 substantially daily.
12. The use according to claim 10, wherein about 10,000 units of interleukin-2 is used per kilogram of the subject's body weight.
13. The use according to claim 10, wherein about 20,000 units of interleukin-2 is used per kilogram of the subject's body weight.
14. A use according to claim 10, wherein the interleukin-2 is used for at least two days.
15. A use according to claim 14, wherein the interleukin-2 is used for about four days.
16. A use according to claim 14, wherein the interleukin-2 is used for about ten days.
17. A use of a pharmaceutical composition comprising an amount of -10-~
recombinant methionyl human interleukin-2 alanine 125 or recombinant human interleukin-2 serine 125 from at least 1,000 to 40,000 units per kilogram of body weight and a pharmaceutically acceptable carrier for treating a human subject for a pre-existing condition of psoriasis by intravenous bolus injection.
recombinant methionyl human interleukin-2 alanine 125 or recombinant human interleukin-2 serine 125 from at least 1,000 to 40,000 units per kilogram of body weight and a pharmaceutically acceptable carrier for treating a human subject for a pre-existing condition of psoriasis by intravenous bolus injection.
18. A use of a pharmaceutical composition comprising an amount of recombinant methionyl human interleukin-2 alanine 125 or recombinant human interleukin-2 serine 125 from at least 1,000 to 40,000 units per kilogram of body weight and a pharmaceutically acceptable carrier for the production of a medicament for treating a human subject for a pre-existing condition of psoriasis by intravenous bolus injection.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1993/008953 WO1995008340A1 (en) | 1993-09-21 | 1993-09-21 | Method for treating psoriasis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2188871A1 CA2188871A1 (en) | 1995-03-30 |
| CA2188871C true CA2188871C (en) | 2001-01-23 |
Family
ID=22236983
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002188871A Expired - Fee Related CA2188871C (en) | 1993-09-21 | 1993-09-21 | Method for treating psoriasis |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU5134693A (en) |
| CA (1) | CA2188871C (en) |
| WO (1) | WO1995008340A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103536905A (en) * | 2013-10-28 | 2014-01-29 | 中国医学科学院基础医学研究所 | Application of interleukin-2 in preparation of medicament for treating psoriasis |
| WO2016025385A1 (en) | 2014-08-11 | 2016-02-18 | Delinia, Inc. | Modified il-2 variants that selectively activate regulatory t cells for the treatment of autoimmune diseases |
| US20170204154A1 (en) | 2016-01-20 | 2017-07-20 | Delinia, Inc. | Molecules that selectively activate regulatory t cells for the treatment of autoimmune diseases |
| US11077172B2 (en) | 2016-11-08 | 2021-08-03 | Delinia, Inc. | IL-2 variants for the treatment of psoriasis |
-
1993
- 1993-09-21 AU AU51346/93A patent/AU5134693A/en not_active Abandoned
- 1993-09-21 WO PCT/US1993/008953 patent/WO1995008340A1/en active Application Filing
- 1993-09-21 CA CA002188871A patent/CA2188871C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| AU5134693A (en) | 1995-04-10 |
| WO1995008340A1 (en) | 1995-03-30 |
| CA2188871A1 (en) | 1995-03-30 |
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| MKLA | Lapsed |