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
2000-12-01
2004-11-02
Chan, Christina (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...
C424S193100, C530S324000
Reexamination Certificate
active
06811782
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of peptide conjugate compositions as an immunogen, with each peptide conjugate contained therein comprising a target antigenic site on the third constant domain (CH3) of the to epsilon (&egr;) heavy chain of IgE, with said target antigenic site covalently linked to (1) a carrier protein through chemical coupling, or (2) a helper T cell epitope and other immunostimulatory sequences through chemical coupling or through direct synthesis, for the treatment of allergy.
More particularly, the present invention relates to the use of such peptide conjugate compositions as an immunogen to elicit the production, in mammals including humans, of high titer polyclonal antibodies specific to a target effector site on the CH3 domain of the &egr; heavy chain of IgE, and to the use of such composition as a pharmaceutical to provide an immunotherapy for IgE-mediated allergic diseases.
BACKGROUND OF THE INVENTION
In the immune system of humans and other mammals, IgE mediates type I hypersensitivities. These are the allergic responses to certain foods, drugs, and environmental allergens which are manifested by such symptoms as allergic rhinitis, asthma, allergic dermatitis, and anaphylaxis. Existing strategies to treat allergic diseases are of limited utility, consisting of attempts to either desensitize the atopic individual to an identified allergen or to ameliorate an ongoing allergic reaction with therapeutic compounds. Limitations to allergen-based desensitization immunotherapy include difficulties in identifying the allergen involved and the adverse reactions frequently caused by the use of the identified allergen (World Health Organization and International Union of Immunological Societies Working Group,
Lancet
, 1989; i:259-261). Other treatments for the relief of allergies employ therapeutic compounds to block the acute inflammatory cascade that is responsible for allergic reactions. These compounds include anti-histamines, decongestants, &bgr;
2
agonists, and corticosteroids. Anti-histamines, decongestants, and &bgr;
2
agonists act on events downstream of IgE in the allergic cascade, making them palliative remedies which address allergic symptoms rather than preventative treatments which must act on events closer to the initiation of IgE-mediated allergic reactions. These palliative remedies provide relief that is short term and partial, frequently accompanied by adverse side effects. Many patients with severe allergies are effectively treated with corticosteroids. Steroid therapy reduces inflammation but is broadly immunosuppressive.
To avoid the shortcomings of the known therapeutic drugs, it would be more desirable to prevent allergic responses by selective intervention targeted to IgE. In common with the other immunoglobulins, IgE has two heavy chains and two light chains. The &egr; heavy chain has five domains, a variable VH domain and constant domains CH1 to CH4. The constant domains from both &egr; chains of an IgE molecule combine to comprise the constant or Fc region of IgE. IgE circulates and becomes attached to effector cells such as basophils and mast cells through a site on the IgE Fc region, becoming bound to a high affinity Fc&egr;RI receptor on the cell surface. In an allergic response, allergens (e.g., pollen, dust mite proteins, flea antigens) bind to the antigen-binding sites on the variable region of mast cell or basophil-bound IgE. This action crosslinks the IgE molecules and the underlying Fc&egr;RI receptors. The IgE-allergen complexes thereby signal the degranulation of mast cells and basophils with the concomitant release of histamine and the other inflammatory mediators. These mediators produce the symptoms of allergy, up-regulate the production of IgE, and result in heightened sensitivity to the allergen (Davis et al.,
Springer Semin Immunopathol
, 1993; 15: 51-73).
It has been suggested that allergic diseases may be treated by interventions which inhibit the binding of IgE to mast cells and basophils. For example, synthetic peptides corresponding to various sites on the Fc of IgE have been studied as competitive inhibitors for the binding of IgE to the Fc&egr;RI receptor, The presumption of the investigators has been that such peptides act as antagonists for sites on IgE that participate in the binding of IgE to the Fc&egr;RI receptor, and serve to map portions of the binding site.
The amino acid residues of the competitively inhibiting IgE peptides and of all IgE peptides to follow, including non-human IgE peptide homologues, are indexed in accordance with the numbering for human IgE given by Dorrington and Bennich, (
Immunol Rev
, 1978; 41: 3-25, also accessible at internet location http:/www.pdb.bnl.gov/pdb.bin/pdbids). That human sequence is listed here as SEQ ID NO:1 and is numbered as shown in Table 1. The homologous dog, rat and mouse sequences for IgE (Patel et al.,
Immunogenetics
, 1995; 41: 282-286; Steen et al.,
J Mol Biol
, 1984; 177: 19-32; and, Ishida et al.,
EMBO
, 1982; 1: 1117-1123) are also shown in Table 1 and listed as SEQ ID NOS: 2, 3, and 4 respectively. The animal sequences are shown in register with human IgE. Individual amino acid positions in human IgE, and in homologues from other species, are identified herein according to the numbering system for the amino acid sequences shown in Table 1, unless otherwise specified.
Helm et al. (
Nature
, 1988; 331:180-183) have shown that a 76 amino acid long recombinant polypeptide, spanning the C-terminal CH2 and N-terminal CH3 region of human IgE, from amino acids 301-376, reduces binding of IgE to human mast cells by competitive inhibition. Other studies reported that only the CH3 domain is involved with binding to Fc&egr;RI. For example, a rat sequence peptide corresponding to amino acids 401-415 of the human sequence (Table 1) inhibited the binding of rat IgE to rat mast cells (Burt and Stanworth,
Eur J Immunol
, 1987; 17:437-440). A peptide of residues 419 to 463 from human IgE prevented the sensitization of rat mast cells (Nio et al.,
FEBS Lett
, 1992; 314: 229-231). Jardieu and Presta (WO 93/04173) reported on peptides homologous to the CH3 and CH4 regions which may include amino acids 373-390, 420-428, 446-453, and adjacent regions, which differentially bind to the Fc&egr;RI receptor. However, high concentrations of all such peptides were required to achieve effective inhibition of IgE binding. These high concentrations are predictive of excessively large doses for significant physiological effect, and are not therapeutically practical.
Anti-IgE antibodies have also been applied as a method for mapping sites on IgE that participate in binding to the Fc&egr;RI receptor. Studies with mouse monoclonal antibodies directed against various domains of IgE Fc revealed that anti-IgE monoclonal antibodies with specificities for the CH3 domain inhibit the binding of IgE to its high affinity receptor (Baniyash et al.,
Molec Immunol
, 1988; 25: 705-711; and, Stadler et al.,
Immunol Cell Biol
, 1996; 74: 195-200). These monoclonal antibody studies are in agreement with earlier studies that used polyclonal antipeptide antibodies to map sites that are apparently involved in receptor binding. For example, rabbit antibodies with specificities for IgE amino acid positions 401-415 (Burt et al.,
Molec Immunol
, 1987; 24: 379-389), and 355-368 (Robertson and Liu,
Molec Immunol
, 1988; 25:103-113) showed specificity for unbound IgE but reacted poorly with receptor-bound IgE.
A canine IgE peptide fragment containing at least five continuous amino acids from dog IgE amino acids 356-479 is useful for the preparation of antibodies for diagnosis of allergy in dogs (JP 9179795, 1997). Those results are suggestive of surface-exposed effector sites in the CH3 domain of the dog &egr; chain, but no such effector site is taught nor is a therapeutic application disclosed for the anti-IgE antibodies.
These epitope mapping studies demonstrate most consistently that the CH3 domain of the &egr; heavy chain can be targeted for interventions aimed at
Walfield Alan M.
Wang Chang Yi
Chan Christina
Huynh Phuong N
Morgan & Finnegan , LLP
United Biomedical Inc.
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