Treatment of allergic rhinitis

Details Treatment of allergic rhinitis Treatment of allergic rhinitis

2002-03-01

2004-09-21

Tate, Christopher R. (Department: 1651)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S012200, C530S300000, C530S324000, C530S325000, C530S350000, C530S855000, C530S858000

Reexamination Certificate

active

06794360

ABSTRACT:

The present invention relates to the discovery that various proteins isolated from ticks are effective in the treatment and prevention of allergic rhinitis. These proteins may most suitably be applied to an affected area and are effective to treat this condition and to ameliorate its symptoms.
Allergic rhinitis is the medical term given to the inflammation of the nasal mucosa caused by allergens such as pollen or dust. There are two general types of allergic rhinitis, seasonal and perennial. Seasonal allergic rhinitis is normally referred to as hay fever and is usually caused by mould or pollen. Perennial allergic rhinitis is usually caused by an inherent sensitivity to one or more types of allergen. This condition generally continues throughout the year or for as long as the patient is exposed to the allergen. The condition is thought to affect more than 15% of the population of the western world.
Both types of allergic rhinitis involve a type 1 (IgE-mediated) hypersensitivity that leads to inflammation. This inflammation is thought to be caused by an excessive degranulation of mast cells and of blood-borne basophils in response to certain allergens. This leads to increased IgE levels and the concomitant release of inflammatory mediators, such as histamine, and of chemotactic factors, such as cytokines, prostaglandins and leukotrienes, that result in a localised inflammatory reaction.
In many cases, prevention of allergic rhinitis can be maximised by avoiding contact with the causative allergen, since even the best medical therapies currently available are ineffective in the face of a high allergen load. However, this is not always possible or practical.
A number of interventional approaches are widely used, including the use of intranasal vasoconstrictors, intranasal and systemic antihistamines, intranasal glucocorticoids, mast cell stabilisers, such as cromolyn compounds, and oral decongestants. One problem with some of the more well-established treatments is that they have a sedative effect, so causing a decrease in patient performance, alertness and cognitive function. Although some non-sedating histamine H1 antagonists are now available, there is a great need for the identification of other non-sedative agents that are effective in the treatment of this condition.
Conventional H
1
receptor antagonists are widely used as antihistamine agents for treating allergic reactions including allergic rhinitis (hay fever), urticaria, insect bites and drug hypersensitivities. H
1
receptor antagonists target the redness and inflammation that is associated with these conditions. However, there are numerous undesirable effects of the H
1
receptor antagonists currently used. When used for purely antihistamine actions, all of the effects on the central nervous system (CNS) are unwanted. When used for their sedative or anti-emetic actions, some of the CNS effects such as dizziness, tinnitus and fatigue are unwanted. Excessive doses can cause excitation and may produce convulsions in children. The peripheral anti-muscarinic actions are always undesirable. The commonest of these is dryness of the mouth, but blurred vision, constipation and retention of urine can also occur. Unwanted effects not related to the drug's pharmaceutical action are also seen. Thus, gastrointestinal disturbances are fairly common while allergic dermatitis can follow topical application of these drugs.
H
2
receptor antagonists are also used as antihistamine agents. These agents target the itching that is associated with the condition as a result of activation of certain aspects of the nervous system.
It can therefore be seen that drugs used to control the actions of histamine are not always effective. The reasons why they may have limited efficacy may relate to the specificity of these drugs for only a sub-class of histamine receptors, particularly when a certain class of conditions requires interference with a larger class of receptors. Indeed, it is now known that there are a large number of different chemoattractants and vasoactive substances implicated in allergic rhinitis, liberated not only by mast cells but also by eosinophils and other cells, that produce undesirable symptoms in patients with allergic disorders.
There is thus a great need for agents that are effective in ameliorating the symptoms of this condition, but that do not generate the side-effects that detract from their attractiveness as therapeutic compounds.
Molecules that are capable of binding to histamine have previously been identified in blood-feeding ectoparasites, such as ticks. For example, a salivary nitric oxide-carrying haeme protein (nitrophorin) of the triatome bug
Rhodnius prolixus
has been found to bind histamine (Ribeiro & Walker, 1994). The isolation of a family of vasoactive amine binding proteins from ticks is described in co-pending International Patent Application No. PCT/GB97/01372, owned by the Applicant for the present invention. The contents of this application are incorporated into the present application in their entirety. These proteins bind to histamine and are closely related to one another. Some of these molecules also bind to serotonin. These molecules differ markedly from any of the H
1
, H
2
or H
3
receptor families and appear to bind to histamine in a different manner.
The present invention is based on the discovery that these tick proteins, and molecules based on their structure, are effective in the treatment of allergic rhinitis.
SUMMARY OF THE INVENTION
According to the present invention there is provided the use of a histacalin protein in the manufacture of a medicament for the treatment or prevention of allergic rhinitis.
The present invention also provides a method for the treatment or prevention of allergic rhinitis which comprises administering to a subject an effective amount of a histacalin protein.
The term “histacalin protein” in the present application denotes:
(a) any vasoactive amine binding protein that binds specifically to a vasoactive amine with a dissociation constant of less than 10
−7
M and which belongs to the same protein family as the proteins MS-HBP1, FS-HBP1 and FS-HBP-2 disclosed in co-pending International Patent Application No. PCT/GB97/01372 wherein a protein is considered to belong to this protein family if the primary, mature monomer sequence of the protein has no more than 260 amino acids and at least 30 of the amino acids in the protein's complete sequence are conserved as identical residues in an alignment of that protein and the proteins MS-HBP1, FS-HBP1 and FS-HBP-2, the alignment preferably having been obtained using GCG's pileup command (Program Manual for the Wisconsin Package, 1994; gap creating penalty=3; gap extension penalty=1, scoring matrix Blosum62.cmp, pileup carried out using the endweight option);
(b) a protein from a haematophagous arthropod that binds specifically to histamine with a dissociation constant less than 10
−7
M and which contains the sequence motifs D/E A W K/R (preferably DAWK, more preferably QDAWK) and Y/C E/D L/I/F W (preferably Y/C ELW);
(c) a natural biological variant, such as an allelic variant or a geographical variant, of a protein as defined in (a) or (b) above;
(d) a functional equivalent of a protein as defined in (a), (b) or (c) above that contains single or multiple amino-acid substitution(s), addition(s), insertion(s) and/or deletion(s) from the wild type protein sequence and/or substitutions of chemically-modified amino acids that do not affect the biological function of binding to its respective vasoactive amine;
(e) an active fragment of a protein as defined in (a), (b), (c) or (d) above, wherein “active fragment” denotes a truncated protein that retains the biological function of binding to its respective vasoactive amine; and
(f) a fusion protein comprising a protein as defined in (a), (b), (c), (d) or (e) above fused to a peptide or other protein, such as a label, which may be, for instance, bioactive, radioactive, enzymatic or fluorescent, or an antibody.
An alignment of the

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