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
1998-09-30
2001-01-09
Mertz, Prema (Department: 1647)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S184100, C530S351000, C514S002600, C514S009100, C514S012200, C514S013800
Reexamination Certificate
active
06171590
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel compositions and methods for inhibiting inflammatory responses associated with autoimmune diseases. In particular, it relates to vaccination with peptides from the extracellular regions of chemokine receptor molecules.
Chemokines constitute a family of small molecular weight cytokines that are produced in inflammation and regulate leukocyte recruitment. These molecules are ligands for seven transmembrane G protein linked receptors that induce a signaling cascade costimulation for T cell activation in addition to participating in transendothelial migration of leukocytes (Oppenheim et al.
Ann. Rev. Immunol
. 9:617-648 (1991), Premback et al.
Nat. Med
. 2:1174-1178 (1996)). Two subfamilies of chemokines, referred to as CC and CXC, have been discovered. CC and CXC chemokines are distinct from each other in their N terminal amino acid sequence which starts either with cysteine-cysteine or cysteine-X-cysteine where X is typically another L-amino acid. They are also distinct in their binding pattern to their receptors. For example, the CC chemokines bind to CC receptors and not to CXC receptors and vice versa.
Different chemokines regulate the trafficking of distinct populations of hemopoietic cells by activating specific 7-transmembrane receptors expressed by these cells (Baggiolini et al.
Adv. Immunol
. 55:97-179 (1994); Gerard et al.
Curr. Opin. Immunol
. 6:140-145 (1994)). Recent publications indicate that the Th1 and Th2 subsets of regulatory T cells are uniquely characterized by the chemokine receptors CXCR3 and CCR3, respectively (Sallusto, et al.
J. Exp. Med
. 187:875-883 (1998); Bonecchi, et al.
J. Exp. Med
. 187:129-134 (1998); Qin, et al.
J. Clin Invest
. 101:746-754 (1998)). Several studies have correlated the expression of three specific chemokines, IP-10, RANTES, and MCP-1, produced by astrocytes in the CNS with the presence of inflammatory infiltration within this tissue during the early phase of EAE (Ransohoff, et al.
FASEB J
. 7:592-600 (1993); Glabinski et al.
Am. J. Pathol
. 150:617-630 (1995) Godiska, et al.
J. Neuroimmunol
. 58:167-176 (1995); and Eng et al.
Neurchem. Res
. 21:511-525 (1996)). While all three chemokines have been shown to be capable of recruiting T lymphocytes in certain experimental models, IP-10 has been demonstrated to be specific for this lineage of hemopoietic cells (Taub et al.
J. Exp. Med
. 177:1809-1814 (1993)); Carr, etal.
Proc. Natl. Acad. Sci. USA
91:3652-3656 (1994); and Farber,
J. Leukoc. Biol
. 61:246-257 (1997). MBP-immunized rats intrathecaly infused with an antisense phosphorothioate oligonucleotide to crg-2 (the murine homologue of human IP-10) show reduced disease clinical score of EAE (Wojcik, et al.
J. Pharmacol. Exp. Ther
. 278:404-410 (1996)).
In addition, higher expression of some of the chemokine receptors such as CXCR3 on IL2 activated human T lymphocytes and not on resting T lymphocytes has been demonstrated (Loetscher et al.
J. Exp. Med
. 184:963-969 (1996)).
Multiple sclerosis (MS) is a T cell-dependent autoimmune disease caused by localized demyelination in the central nervous system (CNS), with only limited therapeutic options available to patients. Extensive investigation has indicated that these autoreactive T lymphocytes frequently, though not always, express the Th1 phenotype of high level production of IFNg, IL-2 and TNFa, with little to no IL-4, IL-5 and IL-10.
Current therapeutics for autoimmune diseases, such as MS, involve the use of antiinflammatory agents or general immunosuppressants. Prior art methods for controlling autoimmune disease fail to provide a simple self-mediated method for specifically eliminating inflammatory responses mediated by chemokines associated with the autoimmune responses. The present invention addresses these and other needs.
SUMMARY OF THE INVENTION
The present invention provides methods of inducing an immune response against a chemokine receptor molecule in a patient. The methods comprise administering to the patient an immunologically effective amount of a pharmaceutical composition comprising an adjuvant and an immunogenic chemokine receptor polypeptide from a extracellular region of a chemokine receptor molecule, for example CXCR3.
The immunogenic peptides are preferably conformationally constrained, for example by cyclization. The length of the immunogenic peptide is not critical to the invention. Typically, the peptide consists of between about 10 and about 50 residues, more often between about 15 and about 30 residues. Exemplary immunogenic peptides of the invention include MVLEVSDHQVLNDAEVAALL (SEQ ID NO:1), ENFSSSYDYGENESDSCCTS (SEQ ID NO:2), PPCPQDFSLNFDRAFLPA (SEQ ID NO:3), DAAVQWVFGSGLCKV (SEQ ID NO:4), SAHHDERLNATHCQYN (SEQ ID NO:5), FPQVGRTALRVLQLVAG (SEQ ID NO:6), and DILMDLGALARNCGRESRVDVAKS (SEQ ID NO:7).
The immunogenic peptides can be administered by any of a number of means. Typically they are administered parenterally. The adjuvant can be, for example, alum.
In preferred embodiments, the method are used to inhibit recruitment of T cells to inflammation sites in a patient. Typically the inflammatory response is associated with an autoimmune disease, such as multiple sclerosis.
The invention also provides pharmaceutical compositions suitable for use in the above methods.
Definitions
The term “peptide” is used interchangeably with “oligopeptide” or “polypeptide” in the present specification to designate a series of residues, typically L-amino acids, connected one to the other typically by peptide bonds between the &agr;-amino and carbonyl groups of adjacent amino acids.
The term “cyclic peptide” refers to peptides in which the N-terminal residue is linked to the C-terminal residue either directly or through an intermediate. Examples of links between the two residues include disulfide bonds and thioether linkages as described below.
An “immunogenic chemokine receptor polypeptide” of the present invention is a polypeptide capable of eliciting an immune response against a chemokine receptor molecule associated with inflammation in autoimmune responses in a patient, such as multiple sclerosis. As set forth in more detail below, the sequence of residues in the polypeptide will be identical to or substantially identical to a polypeptide sequence in a chemokine receptor molecule. Thus, a polypeptide of the invention that has a sequence “from a extracellular region of a chemokine receptor molecule” is polypeptide that has a sequence either identical to or substantially identical to the naturally occurring chemokine receptor amino acid sequence of the region.
As used herein a “extracellular region” of a chemokine receptor molecule is a region of the molecule which is exposed on the surface of a cell expressing the native molecule.
FIG. 1
provides a schematic of the extracellular domains of the human CXCR3 molecule. This molecule has four extracellular regions designated as SP-1, SP-2, SP-3 and SP-4, starting from the N-terminus.
As used herein, the term “adjuvant” refers to any substance which, when administered with or before an antigen, increases and/or qualitatively affects the immune response against the antigen in terms of antibody formation and/or the cell-mediated response. Exemplary adjuvants for use in the present invention are provided below.
The phrases “isolated” or “biologically pure” refer to material which is substantially or essentially free from components which normally accompany it as found in its native state. Thus, the chemokine receptor polypeptides of this invention do not contain materials normally associated with their in situ environment, e.g., other surface proteins on T cells. Even where a protein has been isolated to a homogenous or dominant band, there are trace contaminants in the range of 5-10% of native protein which co-purify with the desired protein. Isolated polypeptides of this invention do not contain such endogenous co-purified protein.
The term “residue” refers to an amino acid or amino acid mimetic incorporated in a oligopeptide by an amide bon
Arimilli Subhashini
Deshpande Shrikant
Ferlin Walter
Howard Maureen
Corixa Corporation
Hamud Fozia
Mertz Prema
Townsend and Townsend & Crew LLP
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