Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-08-10
2002-08-27
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S018700, C514S517000, C514S518000
Reexamination Certificate
active
06440938
ABSTRACT:
The present invention relates to the prevention and/or treatment of allergic conditions and more particularly to such conditions in which a potential allergen must traverse an epithelial barrier. The invention has particular, but not sole, application to the prevention and/or treatment of asthma.
Asthma is the most common chronic disease of childhood and a major debilitating and life threatening condition. It is characterised by acute hypersensitivity, chronic bronchial reactivity and damage and disruption to lung epithelium.
A primary risk factor for asthma is the sensitisation of the lung to airborne allergens such as proteins excreted in the faecal pellets of house dust mites (HDM) belonging to the genus Dermatophagoides (e.g. D pteronyssinus, D. Farinae). When inhaled, HDM faecal pellets impact upon the fluid-covered epithelial surface of large diameter airways. The resulting hydration of HDM faecal pellets will trigger a rapid and total discharge of the major allergenic proteins thus achieving a high local concentration of HDM proteins on the airway lining. Sensitisation involves allergen detection by antigen presenting cells which are normally protected from the environment by the lung epithelium. The mechanism by which the allergens are able to traverse the epithelial barrier is not fully understood.
There is now an increasing body of evidence that several major allergens from HDMs exhibit catalytic competence as enzymes and this has prompted suggestions that these enzymatic actions might be important in allergic sensitisation and to the perpetuation of established allergic inflammatory reactions.
Most data concerning proteinase activity in mite allergens currently relate to those of groups 1, 3, 6 and 9 from mites of the genus Dermatophagoides. The group 1 allergens are cysteine proteinases and have been the subject of greatest scrutiny whereas a lesser amount of information exists concerning the enzymatic effects of the group 3, group 6 and group 9 allergens which share sequence identity with archetypal serine proteinases and which are themselves catalytically competent.
It has been proposed that the cysteine proteinase activity is important in exacerbating the allergic response in asthma because it cleaves CD23, a low affinity IgE receptor, on the surface of antibody producing cells. Cleavage results in positive feedback that causes an increase in igE secretion, thus augmenting the allergic response. On this basis, WO-A-97/04004 (Peptide Therapeutics) proposes that inhibitors of cysteine proteinases may be used inter alia for asthma prophylaxis. However we do not believe that the mechanism proposed in WO-A-97/04004 is likely to operate in vivo. The reason for this is that all experiments on cleavage of CD23 have been carried out on cells in culture and the concentrations of Der p 1 required to produce cleavage were in our view unrealistically large. The cells concerned would, in vivo, be located in the tissues or the blood. It is, in our view, extremely unlikely that allergen concentrations would reach the levels required to produce CD23 cleavage on these locations. There is no evidence that they do, nor that CD23 cleavage takes place in vivo.
Kalsheker N. et al. (1996) Biochem. Biophys. Res. Comms. (USA) 221/1 pages 59-61 discloses that the serine proteinase &agr;
1
-antitrypsin protects the lower respiratory tract from damage by proteinases released in the lung during inflammation. The cysteine proteinase Der p1 is shown to cleave the proposed reactive loop of the serine proteinase inhibitor &agr;
1
-antitrypsin and this mechanism is proposed as being important in the pathogenesis of asthma. Also disclosed is that &agr;
1
-antitrypsin deficiency is linked to the incidence of childhood asthma. However there is no disclosure of how allergic conditions (such as asthma) in which an allergen must traverse an epithelial barrier may be treated or prevented.
Stewart G. et al. (1991)Int. Arch. Allergy Appl. Immunol. 95/2-3 pages 248-256 discloses that dust mite faeces contains three serine proteinases and a cysteine proteinase along with various other enzymes. It also discloses that the cysteine proteinase and at least one of the serine proteinases are allergenic. However there is no disclosure of how allergic conditions such as asthma in which an allergen must traverse an epithelial barrier may be treated or prevented.
In spite of the considerable effort which has taken place in the field of asthma research, there remains a need for improved methods for the prevention and/or treatment of asthma (and other allergic conditions in which a potential allergen most traverse an epithelial barrier).
In its first, broadest aspect the invention provides for the prevention and/or treatment of allergic conditions (of the type in which a potential allergen must traverse an epithelial barrier) by the inhibition of cysteine proteinase activity and serine proteinase activity.
The invention is applicable particularly (but not exclusively) to the treatment of asthma for which the cysteine proteinase activity to be inhibited is preferably that of Der p 1 whereas the serine proteinase activity to be inhibited may be that of any serine proteinase other than trypsin, preferably an allergen serine proteinase and more preferably Der p 3, Der p 6 and/or Der p 9.
The invention has been based on our experimental studies (set out in more detail below) which have demonstrated that the key initial step in allergic sensitisation to house dust mite allergens is mediated by both cysteine and serine proteinase activity. We have found that this activity causes disruption of tight junctions between the cells of the epithelium thus increasing epithelial permeability and permitting the allergen to traverse the epithelium. By this means, the allergens may gain access to, and interact with, dendritic antigen presenting cells to produce an allergic response. Cysteine proteinase inhibitors inhibit the cysteine proteinase allergens but not the serine proteinase allergens and so do not completely block tight junction breakdown. Similarly, serine proteinase inhibitors block the effects of serine proteinase allergens but not the cysteine proteinase allergens and so do not completely block tight junction breakdown. Partial inhibition would still allow an allergic response to be produced. Inhibition of both the cysteine and serine proteinase activity of the allergens is necessary to inhibit disruption of the tight junctions completely and thus the generation of an allergic response.
Although the invention is applicable particularly to the prevention and/or treatment of asthma it may be applied to a range of other allergic conditions including rhinitis, allergic conjunctivitis, atopic dermatitis and food allergies.
The treatment and/or prevention of the allergic condition may be effected by means of
(i) a formulation (which provides a second aspect of the invention) having cysteine and serine proteinase inhibitory activity; or
(ii) a kit (which provides a third aspect of the invention) comprising an inhibitor of cysteine proteinase activity and an inhibitor of serine proteinase activity.
In the formulation of the second aspect of the invention, a single inhibitor compound may provide the required inhibition of serine and cysteine protease activity. However, more usually, and in accordance with a preferred embodiment of the second aspect of the invention, the inhibition of cysteine proteinase activity and serine proteinase activity will be provided by separate inhibitor compounds.
Where separate inhibitory compounds are used as in the kit of the third aspect of the invention, they may be used simultaneously with each other or sequentially.
If necessary more than one type of cysteine proteinase activity and/or more than one type of serine protease activity may be used to provide the required spectrum of activity.
The invention is applicable principally (but not exclusively) to therapeutic treatments.
Therefore according to a fourth aspect of the invention there is provided the use of an inhibitor of cysteine proteinase ac
Garrod David R.
Robinson Clive
Fay Zohreh
Kwon Brian-Yong
The Victoria University of Manchester
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