Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
1998-04-19
2002-12-03
Nolan, Patrick J. (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S184100, C424S248100, C424S283100, C424S282100, C514S013800
Reexamination Certificate
active
06488933
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to vaccine therapy for T-cell mediated diseases, and in particular to therapeutic preparations comprising antigens recognized by T cells involved in the pathogenesis of T cell mediated diseases, such as autoimmune diseases, and a metabolizable lipid emulsion as a biologically active carrier.
BACKGROUND OF THE INVENTION
Autoimmune disorders, e.g., insulin-dependent diabetes mellitus (IDDM or type I diabetes), multiple sclerosis, rheumatoid arthritis and thyroiditis, are characterized by reactivity of the immune system to an endogenous antigen, with consequent injury to tissues. These immune responses to self-antigens are maintained by the persistent activation of self-reactive T lymphocytes.
T cells of the CD4 “helper” type have been divided into two groups by the characteristic cytokines they secrete when activated (Mosmann and Coffman, 1989). TH1 cells secrete IL-2, which induces T cell proliferation, and cytokines such as IFN-&ggr;, which mediate tissue inflammation. TH2 cells, in contrast, secrete IL-4 and IL-10. IL-4 helps T cells secrete antibodies of certain IgG isotypes and suppresses the production of TH1 inflammatory cytokines (Banchereau et al., 1994). IL-10 indirectly inhibits TH1 activation by affecting antigen-presentation and inflammatory cytokine production by macrophages (Moore et al., 1993). It is the TH1 cells which contribute to the pathogenesis of organ-specific autoimmune diseases. TH1-type responses also appear to be involved in other T cell mediated diseases or conditions, such as contact dermatitis (Romagnani, 1994).
Peptides suitable for immunologically specific therapy of an autoimmune disease are peptides that are recognized by T cells involved in the pathogenesis of the autoimmune disease. Each autoimmune disease will have its ideal peptide for use in therapy. A disease like multiple sclerosis involving T cells reactive to self-antigens such as myelin basic protein (MBP) (Allegreta et al., 1990) will require a peptide of myelin basic protein for its therapy, as for example those described by Ota et al., 1990.
The present inventors have shown that autoimmune diseases such as type I diabetes mellitus may be treated by administering a suitable peptide in an oil vehicle. NOD mice spontaneously develop type I diabetes caused by autoimmune T cells that attack the insulin-producing &bgr; cells of the islets. The autoimmune attack is associated with T-cell reactivity to a variety of self-antigens including a peptide of the 60 kDa heat shock protein (hsp 60) and peptides of glutamic acid decarboxylase (GAD). Thus, for example, spontaneous diabetes developing in the NOD/Lt strain of mice could be treated with a peptide designated p277 corresponding to positions 437-460 of the human hsp 60 sequence (PCT Patent Publication No. WO90/10449; D. Elias and I. R. Cohen, Peptide therapy for diabetes in NOD mice,
The Lancet
343:704-06, 1994); with variants of the p277 peptide in which one or both cysteine residues at positions 6 and/or 11 have been replaced by valine and/or the Thr residue at position 16 is replaced by Lys (see PCT Publication WO96/19236) and with peptides designated p12 and p32 corresponding to positions 166-185 and 466-485, respectively, of the human hsp60 sequence. See Israel Patent Application No. 114,407 of the same applicant of the present application, filed on Jun. 30, 1995. See also PCT application No. PCT/US96/11375, filed Jul. 1, 1996, claiming priority from said Israel application no. 114,407, the entire contents of which are hereby incorporated by reference.
Peptide therapy for treatment of IDDM using p12, p32, p277 or variants thereof, was found by the present inventors to be effective when the peptide was administered to mice subcutaneously (sc) in an oil vehicle such as an emulsion of mineral oil known as incomplete Freund's adjuvant (IFA). However, IFA as well as complete Freund's adjuvant (CFA; a preparation of mineral oil containing various amounts of killed organisms of Mycobacterium) are not allowed for human use because the mineral oil is not metabolizable and cannot be degraded in the body. Therefore, it would be desirable to discover an effective vehicle for peptide therapy that would be metabolizable.
Several fat emulsions have been in use for many years for intravenous nutrition of human patients. Two of the available commercial fat emulsions, known as Intralipid (“Intralipid” is a registered trade mark of Kabi Pharmacia, Sweden, for a fat emulsion for intravenous nutrition, described in U.S. Pat. No. 3,169,094) and Lipofundin (a registered trade mark of B. Braun Melsungen, Germany) contain soybean oil as fat (100 or 200 g in 1,000 ml distilled water: 10% or 20%, respectively). Egg-yolk phospholipids are used as emulsifiers in Intralipid (12 g/l distilled water) and egg-yolk lecithin in Lipofundin (12 g/l distilled water). Isotonicity results from the addition of glycerol (25 g/l) both in Intralipid and in Lipofundin. These fat emulsions are quite stable and have been used for intravenous nutrition of patients suffering from gastrointestinal or neurological disorders, which prevent them from receiving nutrition orally, and thus they receive the calories needed to sustain life. Usual daily doses are of up to 1 liter daily.
U.S. Pat. No. 4,073,943 issued on Feb. 14, 1978 to Wretlind et al. and U.S. Pat. No. Re. 32,393 issued on May 29, 1990 as reissue patent of U.S. Pat. No. 4,168,308 issued on Sep. 18, 1979 to Wretlind et al., describe a carrier system for use in enhancing parenteral, particularly intravenous, administration of a pharmacologically active, oil-soluble agent, comprising a stable, oil-in-water emulsion containing a pharmacologically inert lipoid as a hydrophobic phase dispersed in a hydrophilic phase, said lipid being dispersed in the emulsion as finely divided particles having a mean particle size less than 1 micron to achieve rapid onset of an acceptable therapeutic effect, said carrier system being used with an effective dose of said pharmacologically active, oil-soluble agent predominantly dissolved in said lipoid at a fraction ratio thereto in the hydrophobic phase, said therapeutic effect being attributable to said effective dose of the active agent. This carrier system is said to be suitable for administration of a water-insoluble or water-soluble, oil-soluble pharmacologically active agent that is predominantly dissolved in the lipoid phase. Examples of such pharmacologically active agents are depressants, anaesthetics, analgesics, stimulants, spasmolytics, muscle relaxants, vasodepressants and diagnostic, e.g. X-ray contrast, agents. The carrier system is said to enhance the diagnostic or therapeutic effect of the agent with a rapid onset accompanied by a reduced incidence of injury to body tissues.
Intralipid has been proposed as a non-irritating vehicle for several adjuvants for use in vaccines such as, for example, 6-O-(2-tetradecylhexadecanoyl)- and 6-O-(3-hydroxy-2-docosylhexacosanoyl)-N-acetylmuramyl-L-alanyl-D-isoglutamine (Tsujimoto et al., 1986 and 1989), avridine (Woodard and Jasman, 1985), N,N-dioctadecyl-N′,N′-bis(2-hydroxyethyl) propanediamine (CP-20,961) (German Patent Application No. DE 2945788; Anderson and Reynolds, 1979; Niblack et al., 1979). Kristiansen and Sparrman, 1983, have disclosed that the immunogenicity of hemagglutinin and neuraminidase in mice is markedly increased after adsorption onto lipid particles constituting Intralipid.
None of the above publications describe the use of Intralipid as a vehicle for peptides in the treatment of autoimmune diseases, nor has there been any disclosure that Intralipid could mediate a shift of the immune response from a TH1-type response to a TH2-type response.
SUMMARY OF THE INVENTION
It has now been found, in accordance with the present invention, that metabolizable lipid emulsions, such as Intralipid and Lipofundin, can act as vehicles for peptide therapy of autoimmune diseases and of other TH1 T cell mediated diseases or conditions. It has been further found that
Cohen Irun R.
Elias Dana
Shinitzky Meir
Ewoldt Gerald R.
Nolan Patrick J.
Winston & Strawn
Yeda Research and Development Co. Ltd.
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