WO1993001717A1 - Modulation and diagnosis of cytokine dysfunctions - Google Patents
Modulation and diagnosis of cytokine dysfunctions Download PDFInfo
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- WO1993001717A1 WO1993001717A1 PCT/US1992/005286 US9205286W WO9301717A1 WO 1993001717 A1 WO1993001717 A1 WO 1993001717A1 US 9205286 W US9205286 W US 9205286W WO 9301717 A1 WO9301717 A1 WO 9301717A1
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Classifications
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P37/00—Drugs for immunological or allergic disorders
Definitions
- Cytokines are natural macromolecular cellular products which can enhance normal cell functions, including those of lymphocytes which, in turn, convey desirable properties termed "immune surveillance.”
- dysregulation of cytokines characterized by aberrancies in production and/or distribution in bodily tissues, can actually cause or aggravate various human diseases.
- This invention describes a facile way of biologically neutralizing the potential damaging effects of dysregulated cytokine and lymphokine states. By judicious use of certain dsRNAs in specific scheduled dosages, further organ damage is
- Cytokine and lymphokine produced by, or targeted to, lymphocytes
- lymphocytes dysfunctions are being progressively linked to serious human diseases.
- No effective remedies have been proposed until those I dislcose herein.
- Even though needed in normal function of bodily cells e.g., bone marrow, immune system, joint function, pulmonary function, etc.
- aberrancies in cytokine production are associated with disease acceleration and morbidity.
- production can consist of: (a) inappropriate production by cells not normally producing certain cytokines, (b)
- TNF Tumor Necrosis Factor
- macrophage/monocyte derived immune mediator which has been implicated in septic shock, cachexia, graft vs. host
- vascular disease and neoplastic diseases vascular disease and neoplastic diseases. Specifically, elevated levels are associated with a poor clinical outcome.
- TNF can also stimulate cells to produce other
- cytotoxic factors which can in turn cause additional cell inflammation, or cell death, even in brain cells (certain cells called oligodendrocytes).
- Interleukins may promote TNF production, such that diseased human hosts often exist in a milieu of not one, but a group, of aberrant (as defined above)
- lymphokines induced through a type of biological cascade effect.
- the therapeutic goals which are the subjects of the present invention, are to biologically neutralize, or convey various levels of control, over a range of aberrant lymphokines which may co-exist in the same individual.
- TNF levels are increased in persons with malignancies above the upper limit of normal which, in children, is approximately 40 nanograms per liter (Saarinen et al,
- IL-1 beta levels are elevated in infants with severe perinatal complications (280 ⁇ 116 picograms per ml; Miller et al, Journal of Pediatrics, 1990, vol. 117, pp 961-965). These studies indicate IL-1, IL-6 and TNF in spinal cord plasma relate to clinical complications in the perinatal period. Concentrations of IL-1 are also related to severity of malaria; see
- TNF production is a normal response to malaria infection, but excessive levels of production predispose the patient to cerebral malaria and a fatal outcome.
- 2'-5' oligoadenylate pathway namely the 2'-5' oligoadenylate pathway (sometimes called the 2'-5'-oligoaldenylate system or 2-5 OAS for short).
- This pathway can be tested in different cell types which, in turn, may be fractionated by different methods such as 2 or 3 color flow cytometry, gradient centrifugation, etc. Specific derangements may
- NK natural killer cells
- B cells involved in antibody production
- CT cytotoxic T cells
- ADCC antibody-dependent cytotoxic cells
- systemic lupus have typically measurable interferonemia (greater than 6 IU by bio assay per ml or equal or greater than 1 IU by RIA).
- interferonemia greater than 6 IU by bio assay per ml or equal or greater than 1 IU by RIA.
- an interferon-specific antibody When patients develop, by contrast, an interferon-specific antibody they may have inactive
- One objective of my invention is to develop the functional or operational equivalent of an antibody, i.e., to "fine tune" the level of extracellular cytokines to those which are relatively non-toxic to the host and may be medically beneficial.
- the dsRNA used in the procedures described herein may be a complex of a polyinosinate and a polycytidylate containing a proportion of uracil bases or guanidine bases, e.g., from 1 in 5 to 1 in 30 such bases (poly I ⁇
- the dsRNA may be of the general formula
- dsRNA examples of dsRNA are discussed below.
- mismatched dsRNA are meant those in which
- mismatched dsRNAs preferred for use in the present invention are based on copolynucleotides selected from poly (C n ,U) and poly (C n ,G) in which n is an integer having a value of from 4 to 29 and are mismatched analogs of
- the dsRNA may be derived from poly(I) ⁇ poly(C) dsRNA by modifying the ribosyl backbone of polyriboinosinic acid (rl n ), e.g., by including 2'-O-methyl ribosyl residues.
- the mismatched complexes may be
- RNA-stabilizing polymer such as lysine and cellulose.
- rl n ⁇ (C 11-14' U) n or rI n ⁇ r(C 29' G) n , are described bv Carter and Ts'o in U.S. Patents 4,130,641 and 4,024,222.
- the dsRNAs described therein generally are suitable for use according to the present invention. The preferred
- mismatched dsRNA is rl n ⁇ (C 11-14 ,U) n or AMPLIGEN® of HEM
- mismatched dsRNA for use in the invention include: - poly (I) ⁇ poly (C 4 ,U)
- dsRNAs suited to the practice of this invention are short dsRNAs of defined structure, for example oligonucleotides of the formula:
- A is a nucleotide which is not I
- U is a nucleotide which base pairs with A.
- the short oligonucleotide may have the structure:
- oligonucleotides may have substitutions in one strand not complementary to nucleotides in the opposite strand.
- these oligonucleotides are stabilized by internal registers of complementary heteropolymer and desirably the lock or hinge or both contain regions of complementary heteropolymer.
- These oligonucleotides desirably have single-stranded tails.
- ILs, TNF- ⁇ and IFNS are immuno regulatory proteins but their dysregulation actually causes tissue pathology.
- IL-1 and TNF share activities including pyrogenicity, activation of T cells, and neutrophil activation. High levels are found in patients suffering from rheumatoid arthritis and other inflammatory diseases.
- dsRNA in certain levels and given in certain schedules, had a novel and unexpected ability to biologically neutralize certain lymphokine actions associated with host morbidity.
- lymphokine activated intracellular biochemical pathway (2'-5 oligo adenylate synthetase) which has as its terminal mediator the protein RNase L.
- the 2'-5'-oligoadenylate/RNase L pathway is illustrated in Fig. 2 of my European application 0285 263 A3 and was assessed using the procedures described in Carter et al The Lancet, 1286-1292 (June 6, 1987).
- elevation is defined as greater than 100, normal in the range of 60 to
- Figure 1 shows a giant cell/HHV-6 assay in which peripheral blood cells from several patients
- peripheral blood the individuals suffered more in terms of cerebral function, suggesting that the aberrant cytokine production was localizing their effects to the central areas (brain) more than the molecules were damaging peripheral body tissues in these particular individuals.
- HHV-6 human herpes virus
- cytokines from human blood cells, including cytokines designated TNF and IL-1, in amounts comparable to those which I discovered dsRNA would biologically neutralize in animals or man.
- panel A Two panels were analyzed for cytokine derangement.
- panel A was analyzed for IL-1-beta protein release after HHV-6 infection of human cells.
- TCID 50 /ml lymphokine/cytokine level
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Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5502798A JPH07501787A (ja) | 1991-07-16 | 1992-06-23 | サイトカイン機能不全の緩和法および診断法 |
| EP19920914799 EP0596912A4 (en) | 1991-07-16 | 1992-06-23 | Modulation and diagnosis of cytokine dysfunctions. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US73022991A | 1991-07-16 | 1991-07-16 | |
| US730,229 | 1991-07-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993001717A1 true WO1993001717A1 (en) | 1993-02-04 |
Family
ID=24934492
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1992/005286 WO1993001717A1 (en) | 1991-07-16 | 1992-06-23 | Modulation and diagnosis of cytokine dysfunctions |
Country Status (11)
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10653619B2 (en) | 2009-03-23 | 2020-05-19 | Medtronic, Inc. | Drug depots for treatment of pain and inflammation |
| USRE48948E1 (en) | 2008-04-18 | 2022-03-01 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4795744A (en) * | 1986-07-17 | 1989-01-03 | Hem Research, Inc. | Modulation of AIDS virus-related events by double-stranded RNAS |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4950652A (en) * | 1987-03-23 | 1990-08-21 | Hem Research, Inc. | dsRNAs for combination therapy in the treatment of viral diseases |
| AU1820388A (en) * | 1987-07-17 | 1989-01-19 | Hem Research, Inc. | Double stranded rna correction of aberrant metabolic pathways associated with uncontrolled tumor cell and virus growth cycles |
| AU1820588A (en) * | 1987-07-17 | 1989-01-19 | Hem Research, Inc. | Double-stranded rna correction of abnormalities in circulating immune complexes and monocyte function |
| CA1320446C (en) * | 1988-06-20 | 1993-07-20 | William A. Carter | Modulation of lymphokine-resistant cellular states by dsrnas |
-
1992
- 1992-06-23 EP EP19920914799 patent/EP0596912A4/en not_active Withdrawn
- 1992-06-23 AU AU22688/92A patent/AU2268892A/en not_active Abandoned
- 1992-06-23 JP JP5502798A patent/JPH07501787A/ja active Pending
- 1992-06-23 CA CA002113573A patent/CA2113573A1/en not_active Abandoned
- 1992-06-23 WO PCT/US1992/005286 patent/WO1993001717A1/en not_active Application Discontinuation
- 1992-07-01 IE IE214592A patent/IE922145A1/en not_active Application Discontinuation
- 1992-07-15 TW TW081105601A patent/TW271398B/zh active
- 1992-07-15 ZA ZA925263A patent/ZA925263B/xx unknown
- 1992-07-15 PT PT100688A patent/PT100688A/pt not_active Application Discontinuation
- 1992-07-15 MX MX9204164A patent/MX9204164A/es unknown
- 1992-07-15 CN CN92105778A patent/CN1068738A/zh active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4795744A (en) * | 1986-07-17 | 1989-01-03 | Hem Research, Inc. | Modulation of AIDS virus-related events by double-stranded RNAS |
Non-Patent Citations (1)
| Title |
|---|
| See also references of EP0596912A4 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USRE48948E1 (en) | 2008-04-18 | 2022-03-01 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
| US10653619B2 (en) | 2009-03-23 | 2020-05-19 | Medtronic, Inc. | Drug depots for treatment of pain and inflammation |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07501787A (ja) | 1995-02-23 |
| MX9204164A (es) | 1993-05-01 |
| TW271398B (enrdf_load_stackoverflow) | 1996-03-01 |
| AU2268892A (en) | 1993-02-23 |
| PT100688A (pt) | 1993-10-29 |
| CA2113573A1 (en) | 1993-02-04 |
| ZA925263B (en) | 1993-03-31 |
| IE922145A1 (en) | 1993-01-27 |
| EP0596912A1 (en) | 1994-05-18 |
| EP0596912A4 (en) | 1994-07-27 |
| CN1068738A (zh) | 1993-02-10 |
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