Immunomodulating compounds comprising d-isomers of amino acids

Details Immunomodulating compounds comprising d-isomers of amino acids Immunomodulating compounds comprising d-isomers of amino acids

1996-05-22

2002-08-20

Nolan, Patrick J. (Department: 1644)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S328000

Reexamination Certificate

active

06436903

ABSTRACT:

TECHNICAL FIELD
The field of this invention is immunomodulation.
BACKGROUND
The immune system plays a crucial role in the defense of mammalian hosts against pathogenic organisms and aberrant indigenous cells, such as in neoplasia. Included in the defense mechanism are cytotoxic T-lymphocytes (“CTL”) which serve to monitor the infection of cells by pathogenic organisms and the presence of neoplastic cells. They also attack cells having a different major histocompatibility complex repertoire from the host. Under certain conditions, the CTL attack indigenous cells, resulting in a group of diseases referred to as autoimmune diseases.
For transplantation and autoimmune diseases one would wish to be able to inhibit the CTLs from attacking the tissue. For the most part, today, in order to inhibit CTLs, immunosuppressants are employed, which generally debilitate the immune system. As a result, the patient is much more susceptible to adventitious infection, as well as numerous side effects resulting from the drugs, such as cyclosporin A and FK506. There is, therefore, substantial interest in providing alternative methods for inhibiting immune attack in the cases of transplantation and in autoimmune diseases, where the inhibition is more specific, has fewer side effects, and may be longer lasting.
Relevant Literature
Clayberger, et al.,
J. Exp. Med
. (1985) 11:1709-1714 describe HLA-A2 antigen in comparisons with HLA-Aw68 and Aw69. Townsend, et al.,
Cell
, (1986) 44:959-968 suggests that CTL recognize segmental epitopes of denatured or degraded proteins in a similar way as helper T-cells. Holmes and Parham,
EMBO J
., (1985) 4:2849-2854 describe the relationship of HLA-A2, Aw68 and Aw69. CTL target specificity has been taught to be extremely sensitive to changes in structure of human Class I molecules (Durna and Pease,
Transplantation
, (1986) 41:279-285: Biddison, et al.,
J. Immunol
., (1980) 124:548-552: Spits, et al.,
Immunogenetics
, (1982) 16:503-512: Gaston, et al.,
J. Exp. Med
. (1983) 158:280-293).
Mutants which affect recognition by CTL have been studied in mice (Nathenson, et al.,
Ann. Rev. Immunol
. (1986) 4:471-502: Schulz, et al.,
Proc. natl. Acad. Sci. USA
(1983) 80:2007-2011) and humans, (Krangel,
Biochemistry
(1982) 21:6313-6321: Krangel, et al.,
J. Immunol
. (1983) 130:1856-1862: Cowan, et al.,
J. Immunol
. (1985) 135:2835-2841: Taketani, et al., ibid (1984) 133:816-821; and Vega, et al.,
Proc. Natl. Acad. Sci. USA
(1985) 82:7394-7398).
These reports have focused considerable attention on the region between residues 147 and 157, although other regions can also produce functional differences (Ezquerra, et al.,
J. Immunol
. (1985) 134:2727-2733). Clusters of variability have been reported at the carboxy-terminal end of the first extracellular domain and at the amino-terminal end of the second extracellular domain (Ways, et al.,
J. Biol. Chem
. (1985) 26:11924-11933). Sequences between residues 105-108 of all Class I molecules are related to that of the fibronectin binding tetrapeptide (Auffray and Novotny,
J. Human Immunology
(1986) 15:381-390), which tetrapeptide in either orientation is found to have cell attachment properties (Pierschbacher and Ruoslahti,
Nature
(1984) 309:30-33; Yamada and Kennedy,
J. Cell. Biol
. (1985) 28:99-104). Substitution at position 107 affecting a single monoclonal antibody defined epitope of HLA-A2 has been reported by Salter, et al.,
J. Exp. Med
. (1987) 166:283-288.
Copending U.S. patent application Ser. No. 08/222,851 filed Apr. 5, 1994, and PCT Application US95/04349 filed Apr. 5, 1995, each disclose class I MHC peptides which regulate cytotoxic T-cell lymphocyte (CTL) activity. Copending U.S. patent application Ser. No. 07/844,716 filed Mar. 2, 1992, and PCT Application US93/01758 filed Mar. 2, 1993, each disclose lymphocyte activity regulation by HLA peptides. The entire disclosure of each of the above mentioned patent applications is incorporated herein by reference.
DISCLOSURE OF THE INVENTION
Methods and compositions are provided for immunomodulation to inhibit cytotoxic T-lymphocytes (“CTL”) from undesirably attacking cells in a host or in vitro. Although the compositions of the invention contain the unnatural“D” forms of amino acids, surprisingly, these compositions exhibit biological activity in modulating the immune system. Inclusion of the unnatural“D” forms is advantageous as it renders the composition less susceptible to degradation in vivo. The compositions include a compound having immunomodulating activity which is a peptide-type compound, or a variant or fragment, including the N-terminal acylated and C-terminal amidated or esterified forms thereof of up to 30 amino acids wherein the peptide-type compound comprises the formula SEQ ID NOS:1 and 2
R aa
76-77
L aa
79-84
or
aa
84-79
L aa
77-76
R
wherein:
aa
76
is E or V;
aa
77
is D, S or N;
aa
79
is R or G;
aa
80
is I or N;
aa
81
is a small or hydrophobic amino acid;
aa
82
is R or L;
aa
83
is G or R; and
aa
84
is a small or hydrophobic amino acid;
wherein
at least one of the amino acids is the D isomer. The compositions are useful for immunomodulation in vitro and in vivo.


REFERENCES:
patent: 5171838 (1992-12-01), Chiba et al.
patent: 5589458 (1996-12-01), Jameson et al.
patent: WO 88/05784 (1988-08-01), None
patent: WO 90/10016 (1990-09-01), None
patent: WO 93/17699 (1993-09-01), None
Karin et al., J. Exp. Med. vol. 180, 2227-2237, 1994, Dec. 1994.*
Nisco et al. J. Immunology, vol. 152:3786-3792, Feb. 1994.*
Buelow et al., Transplantation, vol. 59:455-460, Feb. 1995*
S. Nisco et al., “Induction of Allograft Tolerance in Rats by an HLA Class-1-Derived Peptide and Cyclosporine A1, ”Journal of Immunology(1994) 152:3786-3792.
M.C. Cuturi et al., “Prolongation of Allogeneic Heart Graft Survival in Rats by Administration of a Peptide (a.a. 75-84) from the &agr;1 Helix of the First Domain of HLA-B7 01,”Transplantation(1995) 59:661-669.
Auffray et al.,J. Human Immunology(1986) 15:381-390.
Biddison,.et al.,J. Immunol. (1980) 124:548-552.
Clayberger, et al.,J. Exp. Med. (1985) 11:1709-1714.
Cowan, et al.,J. Immunol. (1985) 135:2835-2841.
Duran, et al.,Transplantation(1986) 41:279-285.
Gaston, et al.,J. Exp. Med. (1983) 158:280-293.
Holmes, et al.,EMBO J. (1985) 4:2849-2854.
Koller, et al.,J. Immunol. (1985) 134:2727-2733.
Krangel,Biochemistry(1982) 21:6313-6321.
Krangel, et al.,J. Immunol. (1983) 130:1856-1862.
Nathenson, et al.,Ann. Rev. Immunol. (1986) 4:471-502.
Pierschbacher, et al.,Nature(1984) 309:30-33.
Salter, et al.,J. Exp. Med. (1987) 166:283-288.
Schulz, et al.,Proc. Natl. Acad. Sci. USA(1983) 80:2007-2011.
Spits, et al.,Immunogenetics(1982) 16:503-512.
Taketani, et al.,J.Immunol. (1984) 133:816-821.
Townsend, et al.,Cell(1986) 44:959-968.
Vega, et al., Proc. Natl. Acad. Sci. USA (1985) 82:7394-7398.
Ways, et al., J. Biol. Chem. (1985) 26:11924-11933.
Yamada, et al., J. Cell Biol. (1985) 28:99-104.
Buelow et al., “Immunomodulation by Soluble HLA Class I,”TransplantationMar. 15, 1995, vol. 59, No. 5, pp. 649-654.

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