Peptides for the treatment of systemic lupus erythematosus

Details Peptides for the treatment of systemic lupus erythematosus Peptides for the treatment of systemic lupus erythematosus

1999-09-20

2001-05-08

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...

C530S326000

Reexamination Certificate

active

06228363

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the use of laminin peptides and laminin derivatives, including R38 peptide and related analogs for the treatment and detection of systemic lupus erythematosus.
BACKGROUND OF THE INVENTION
Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs. Through the involvement of the kidneys in the autoimmune inflammatory process lupus glomerulonephritis is a major cause of morbidity and mortality in this disease (Alarcon-Segovia D. In: Primer on the Rheumatic diseases. Ed. Schumascher H. R. Arthritis Foundation, Atlanta, Ga., (1988) pp. 96-100).
Serologically, the disease is characterized by the occurrence of a variety of autoantibodies in the serum, of which the most prominent are the anti-DNA auto antibodies (Naparstek Y et al Annu. Rev. Immunol. (1993) 11 79-104). Although low titers of anti-DNA antibodies may occur in various inflammatory and autoimmune diseases, high levels are found mainly in SLE, and the combination of high anti-DNA antibodies with low complement levels is virtually diagnostic of SLE (Wallace D. J. et al In: Dubois' Lupus erythematosus. Lea and Febiger, Philadelphia, 1993).
The binding of immunoglobulins to the glomerular basement membrane (GBM) has been shown by the staining of kidneys derived from lupus patients or lupus strains of mice (Wallace D. J. et al supra). It has also been shown that anti-DNA antibodies eluted from the kidneys of a lupus patient as well as from MRL/1pr/1pr mice cross react with sulfated glycosaminoglycans whereas the serum anti-DNA antibodies do not show this cross reactivity (Naparstek Y et al Arthritis Rheum. (1990) 33, 1554-1559). These results have suggested that extracellular matrix (ECM) play a role in pathogenesis of lupus as the target for the nephritogenic autoantibodies.
Temmat R. M. et al J. Autoimmun. (1990) 3 531-545, discloses the cross reaction of components of the ECM, like laminin and heparin with murine monoclonal anti-DNA antibodies.
EP Patent Application EP 670,495 discloses the presence of anti-ECM antibodies in the urine of patients with active lupus. Furthermore this patent application discloses the cross reaction of these antibodies with a 200 kDa laminin component of the ECM, and an assay for SLE based on the detection of these anti ECM/laminin antibodies in urine.
R38 is a peptide sequence isolated from the C-terminal region of the mouse laminin &agr; chain (residues 2890-2910 according to Skubitz et al., J. Cell Biol (1991)115 1137-1148, or residues 2851-2871 according to Sasaki M. et al., J. Biol. Chem. (1988) 263, 16,536-16,544). It is located at the junction of the globular domains of the fourth and fifth loops (peptide GD-2 in Skubitz et al. J Cell Biol (1991) 115 1137-1148) and is comprised of the following amino-acid sequence:
KEGYKVRLDLNITLEFRTTSK (SEQ ID NO. 1)
Current SLE therapy is limited to corticosteroids which suppress the over-reactive immune system. This therapy is not specific and its inevitable side effects may themselves be fatal. Furthermore, immunosuppressive therapy is complicated and its initiation is based on a combination of clinical symptoms, blood serological tests and kidney biopsy. There is therefore a need for a more specific therapy for SLE that will not be associated with the side effects of the immunosuppresive agents as well as a more specific and less invasive assay for the evaluation of disease activity. Indeed a recent review (The Lancet (1995) 310 1257-1261) stated that blood tests though useful in confirming diagnosis of SLE are “less useful in monitoring disease activity.”
None of the above mentioned references disclose the treatment of systemic lupus erythematosus by the administration of the R38 peptide or analogs thereof. Moreover none of the above mentioned references disclose the use of R38 peptide in a diagnostic test for the disease or in monitoring disease activity. The contents of all these patents and all literature references referred to above are hereby incorporated by reference in their entirety.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a method for treating systemic lupus erythematosus comprising the administration of laminin peptides.
Another object of the present invention is to disclose R38′ and other novel analogs and derivatives of R38 peptide, the administration of which comprises a method for treating systemic lupus erythematosus.
A further object of the present invention is to provide a diagnostic test for the disease by using the R38 peptide, R38′ peptide and other structurally related analogs and derivatives thereof.
The invention also relates to pharmaceutical compositions comprising R38 peptide, R38′ peptide and other novel analogs and derivatives of R38 peptide, or pharmaceutically acceptable salts thereof for use in the treatment of SLE.
As used herein the term “R38 peptide” is used to include the R38 peptide itself, analogs, derivative and fragments thereof that retain the activity of the complex peptide. The term analogs is intended to include variants on the peptide molecule brought about by, for example, homologous substitution of individual or several amino acid residues. The term derivative is used to include minor chemical changes that may be made to R38 itself or analogs thereof that maintain the biological activity of R38 and similarly the term “fragments” is used to include shortened molecules of R38.


REFERENCES:
patent: 0670495 (1995-09-01), None
patent: 0765660 (1997-09-01), None
patent: 9204914 (1992-04-01), None
patent: 9604926 (1996-02-01), None
Andria et al., “Diverse VHand VLGenes are Used to Produce Anitbodies Against a Defined Protein Epitope”Journal of Immunology, vol. 144 (1990), 144(7): 2614-2616 (Exhibit 5).
Ben-Yahuda et al., “The Urine of SLE Patients Contains Antibodies that Bind to the Laminin Component of the Extracellular Matrix.”Journal of Autoimmunity, vol. 8, No. 2, 1995, pp. 279-291 (Exhibit 6).
Foster et al., “Molecular Analysis of Spontaneous Nephrotropic Anti-Laminin 151(2): Antibodies in an Autoimmune MRL-Ipr/Ipr Mouse” vol. 151 (1993), J. Immunol 814-824 (Exhibit 7).
Gehlsen et al., “A Synthetic Peptide Derived from the Carboxy Terminus of the Laminin A Chain Represents a Binding Site for the &agr;3B1Integrin” (1992), The Journal of Cell Biology 117(2): 449-459 (Exhibit 8).
Harvath et al. “Laminin Peptides Stimulate Human Neutrophil Motlity ” vol. 117 (1994), J. Immunol. 152: 5447-5456 (Exhibit 9).
Lockshin et al. “Lupus Pregnancy—Case-Control Prospective Study Demonstrating Absence of Lupus exacerbation during or after Pregnancy” vol. 77 (1984), The American Journal of Medicine 77: 893-898 (Exhibit 10).
Sabbaga et al. “A Murine Nephritogenic Monoclonal Anti-DNA Autoantibody binds directly to mouse laminin, the major non-collagenous protein component of the glomerular basement membrane”(1989), Eur. J. Immunol. 19: 137-143 (Exhibit 11).
Sasaki et al. “Laminin, a Multidomain Protein” vol. 263 No. 32 (1988), The Journal of Biological Chemistry of 263(32):16536-16544 (Exhibit 12).
Skubitz et al. “Synthetic Peptides form the Carboxyl-terminal Globular Domain of the A Chain of Laminin: Their Ability to Promote Cell Adhesion and Neurite Outgrowth, and Interact with Heparin and the B1 Integrin Subunit”vol. 115 No. 4 (1991), The Journal of Cell Biology 115(4): 1138-1148 (Exhibit 13).
Termaat et al., “Antigen-specificity of Antibodies Bound to Glomeruli of Mice with Systemic Lupus Erythematosus-Like Syndromes” vol. 68 No. 2 (1993), Laboratory Investigation, 68(2): 164-173 (Exhibit 14).
Wilke et al. “Human Keratinocytes Adhere To Multiple Distinct Peptide Sequences of Laminin.” (1991), The Journal of Investigative Dermatology, 97(1): 141-146 (Exhibit 15); and.

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