Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1998-02-26
2000-03-07
Davenport, Avis M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 2, 514 19, 530331, A61K 3800, A61K 3802, C07K 500, C07K 700
Patent
active
060340665
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to compounds for use in the treatment of allergic diseases including juvenile asthma and eczema.
Compounds of the invention can inhibit IgE mediated reaction to major environmental and occupational allergens. They can also have a prophylactic effect against allergic disease by preventing allergic sensitisation to environmental and occupational antigens when administered to at-risk individuals (e.g. those at genetic risk of asthma, and those exposed to occupational allergens in the workplace). The compounds of the invention can also be useful for inactivation or attenuation of the allergenicity of allergens in situ. The invention provides novel compounds and ligands per se, pharmaceutical compositions containing the compounds, processes for producing the compounds and pharmaceutical compositions, and methods for using the compounds and compositions in treatment or prophylaxis of IgE mediated allergic diseases and in inactivation or attenuation of allergens in situ. The invention also provides means for the reducing or destroying the viability of allergy-causing organisms.
The invention is made possible by our new understanding of the role of the low-affinity receptor for IgE (FceRII), also known as CD23, in IgE mediated allergic diseases.
DESCRIPTION OF THE RELATED ART
The Multiple Roles of CD23 CD23 plays an important role in the regulation of immune responses--particularly the regulation of IgE responses. CD23 is a cell surface protein which extends from the plasma membrane via a stalk which is cleaved proteolytically during immune responses. We have demonstrated that CD 23 is cleaved by Der p I; a protease which is the major allergen of the house dust mite, although the endogenous proteases responsible or cleaving CD 23 have not so far been identified. In its membrane bound form, CD23 acts as a cellular receptor for IgE and is found on various cell types including B cells, T cells, platelets, eosinophils, keratinocytes and also on antigen presenting cells (including follicular dendritic cells) which present antigens to T and B lymphocytes. The level of expression of CD23 at the cell surface determines its functionality and is regulated by cytokines, notably IL4.
In its membrane bound form, CD23 allows eosinophils to attach to parasites via antigen-specific IgE. It also plays an important regulatory role on B lymphocytes (which produce antibodies). In the presence of soluble IgE, probably in the form so immune complexes with the allergen, cell surface CD23 becomes occupied by IgE, conveying an inhibitory signal to the B-lymphocyte. This is believed to be an important negative feedback loop in the regulation of IgE synthesis. Occupancy of membrane bound CD23 by IgE protects CD23 from proteolytic cleavage, preventing the release of "cytokine active" forms of soluble CD23 (see below) which favour the production of IgE as opposed to other classes of immunoglobulin. CD23 also interacts with ligands (or "counterstructures") other than IgE. By association of CD23 on an activated B cell with CD21 (the type two complement receptor "CR2") on a follicular dendritic cell of the lymph node, cell-surface CD23 functions as an intercellular adhesion molecule. This function of CD23 is believed to be important in the rescue of germinal centre B lymphocytes from "apoptosis" (i.e. programmed cell-death), allowing the survival of antibody producing clones which would otherwise have been destined to die. There is also evidence that CD23 associates with the cell-surface molecules responsible for presenting antigenic peptides to T lymphocytes (i.e. the HLA class-II molecules) and may thereby influence antigen presentation to T lymphocytes. Moreover, the presence and degree of expression of CD23 on Langerhans cells (a type of antigen presenting cell), and its affinity for immune complexes comprised of allergen and IgE, will also determine to what extent such complexes are processed and presented to T lymphocytes. CD23 may therefore influence antigen presentation to both B and T lym
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Hart Terrance
Johnson Tony
Laing Peter
Quibell Martin
Shakib Farouk
Davenport Avis M.
Peptide Therapeutics Limited
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