Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Fusion protein or fusion polypeptide
Reexamination Certificate
1998-09-09
2004-04-13
Chan, Christina Y. (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Fusion protein or fusion polypeptide
C424S193100, C424S194100, C424S275100, C514S012200, C530S324000
Reexamination Certificate
active
06719976
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a multi-epitope peptide, which is useful for peptide-based immunotherapy of allergic diseases.
BACKGROUND ART
Allergic diseases are defined to be functional disturbances caused by type I hypersensitivity (type I immune response mediated by IgE antibodies) or a kind of disease induced by the disturbance. The symptoms include pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock. Pollinosis is a representative allergic disease. In Japan, approximately 10% of the population suffers from cedar pollinosis, and the number of the patients is still increasing. In America, 5 to 15% of the population suffers from short ragweed pollinosis. Pollinosis is a serious problem both socially and economically because there are many patients and they suffer from unbearable conditions such as itchiness of eyes, runny noses, sneezing, and nasal congestion. Moreover, once the patient acquires pollinosis, the disease manifests itself every year. An effective therapy for pollinosis has thus earnestly been sought.
To comprehend and treat allergic diseases, it is important to understand how a type I allergic response is developed. Current studies focus on clarifying the initial reaction in the allergen-specific immune response, especially the mechanism of regulating a T cell-mediated allergic reaction. Initiation of an immune response to a foreign antigen including an allergen depends on antigen-presenting cells in the immune system. The antigen-presenting cells (i.e., B cells, macrophages, and dendritic cells) take up incoming foreign antigens, break them down to antigen peptides (T cell epitope peptides), put the fragments in a pocket consisting of &agr; and &bgr; chains of major histocompatibility complex (MHC) class II molecules (HLA class II in human), display the fragments on the cell surface, and thereby present the foreign antigens to antigen-specific CD4 positive helper T cells (Th cells). An HLA class II molecule consists of DR, DQ and DP molecules. The &agr;-chain of the DR molecule is encoded by the HLA-DRA gene, and the &bgr;-chain is encoded by the HLA-DRB1, -DRB3, -DRB4 or -DRB5 gene. The &agr;-chain of the DQ molecule is encoded by the HLA-DQA1 gene, and the, &bgr;chain is encoded by the HLA-DQB1 gene. The &agr;-chain of the DP molecule is encoded by the HLA-DPA1 gene, and the &bgr;-chain is encoded by the HLA-DPB1 gene. Each gene except for HLA-DRA contains many alleles. The pocket in which antigenic peptides are placed is highly polymorphic, and the structures differ slightly from each other. Because of this, the kind of antigenic peptides that bind to the pocket and are presented to T cells is restricted to that structure.
Once Th cells receive HLA class II-restricting antigen information via the T cell receptor (TCR), they are activated to secrete various cytokines, by which they proliferate by themselves. At the same time, the Th cells induce differentiation of B cells into plasma cells, to induce antibody production. Depending upon the difference in the cytokine-producing pattern, the Th cells activated by antigen stimulation are classified into Th 1 cells capable of producing interferon 2 (IL-2), interferon&ggr; (IFN-&ggr;) and lymphotoxin (TNF-&bgr;); Th 2 cells capable of producing IL-4, IL-5, IL-6, IL-10 and IL-13; and Th0 cells capable of producing both cytokines. The production of IgE antibody, which is a cause of allergy, is promoted by IL-4 and IL-13 but suppressed by IFN-&ggr;. That is, Th1 cells suppress IgE production, whereas Th2 cells promote IgE production. In other words, sensitization of allergy is determined by whether Th1 cells or Th2 cells function upon exposure of antigens. It is commonly known that Th2 cells predominantly function in the patients with allergy. Allergen-specific IgE antibodies adhere to peripheral basophil and tissue mast cells. The subsequent exposure of allergen results in cross-linking of the IgE antibody on the basophil or the mast cell via the allergen. This releases inflammatory mediators including histamine, prostaglandins, and leucotriene, thereby causing an immediate allergy response. In response to these inflammatory mediators, lymphocytes, monocytes, basophils, and eosinophils are localized in the inflammatory region of the tissue and result in the release of mediators that cause various reactions including disturbance and a late phase reaction.
One way to treat a particular allergy by antigen-specifically suppressing IgE antibody production is hyposensitization therapy using an allergen protein molecule. Hyposensitization therapy can provide a long-term effect that cannot be achieved by chemotherapy, and hence, is the only treatment close to an effective therapy. However, hyposensitization therapy is not always accepted as a general method for treating allergy, possibly because its mechanism and possible side effects (such as topical swelling or anaphylactic shock) remain unknown.
In place of hyposensitization therapy, a mechanism of hyposensitization using a peptide antigen bearing a T cell epitope has been proposed. The peptide fragment carrying a T cell epitope on the allergen molecule used for this therapy contains no B cell epitope or, if any, is monovalent so that the peptide fails to cross-link an IgE receptor with high affinity on the mast cell. For these reasons, patients administered the peptide fragment should not experience side effects such as anaphylactic shock. It is further known that when T cell epitope is given in vivo, T cells are antigen-specifically inactivated (anergy) (La Salle J. M. et al.: J. Exp. Med. 176: 177-186, 1992). It is reported that based on such a theoretical background, hyposensitization using a peptide carrying major T cell epitopes of cat dander allergen Fel d1 was carried out in an experimental murine model, and T cell anergy was induced in vitro (Briner, T. J. et al.: Proc. Natl. Acad. Sci. USA, 90: 7608-7612, 1994). Clinical trials on hyposensitization using this peptide are now under way (Norman, P. S. et al.: Am. J. Respir. Crit. Care Med. 154: 1623-1628, 1996; Simons, F. E. et al.: Int. Immunol. 8: 1937-1945, 1996). Hyposensitization therapy using such a peptide carrying the major T cell epitope on the allergen molecule is called “peptide-based immunotherapy” (or “peptide-based hyposensitization therapy”).
As a standard for selecting T cell epitope peptides appropriate for the peptide-based immunotherapy, a positivity index (a mean T cell stimulation index multiplied by appearance frequency) is proposed in WO 94/01560. It is also reported that in peptide design, HLA haplotypic variations in a population of patients should be covered (Wallner, B. P. & Gefter M. L.: Allergy, 49: 302-308, 1994).
DISCLOSURE OF THE INVENTION
Generally, allergic patients have specific IgE antibodies to each of two or more allergen molecules differing from each other. For a potent allergy therapy, it is important to develop a peptide-based immunotherapeutic agent effective for these patients. However, such an immunotherapeutic agent has not yet been developed. Even the idea of such an agent has never been published in any of the above literatures. Accordingly, an objective of the present invention is to provide a peptide-based immunotherapeutic agent that is efficacious even for allergy patients sensitive to two or more different allergens.
Cedar pollen contains two major allergens, Cry j 1 (Yasueda, H. et al.: J. Allergy Clin. Immunol. 71: 77-36, 1983) and Cry j 2 (Taniai, M. et al.: FEBS Letter 239: 329-332, 1988; Sakaguchi, M. et al.: Allergy 45: 309-312, 1990). More than 90% of the patients with cedar pollinosis possess specific IgE antibodies to Cry j 1 and Cry j 2; the remaining patients (slightly less than 10%) possess a specific IgE antibody to either Cry j 1 or Cry j 2 (Hashimoto, M. et al.: Clin. Exp. Allergy 25: 848-852, 1995). Use of one or more T cell epitopes from only Cry j 1 or Cry j 2 would be expected to be less effective since IgE from the patients is reactive to both Cry j 1 and Cry j 2. Thus, T cell, eptope
Dairiki Kazuo
Iwama Akiko
Kino Kohsuke
Kume Akinori
Sone Toshio
Chan Christina Y.
DiBrino Marianne
Meiji Milk Products Co. Ltd.
Saliwanchik Lloyd & Saliwanchik
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