Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
1999-10-28
2001-11-06
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S184100, C424S190100, C424S434000, C424S275100, C424S535000, C424S538000, C424S193100
Reexamination Certificate
active
06312711
ABSTRACT:
SUBJECT OF THE INVENTION
The present invention relates to a novel pharmaceutical or food composition intended for treating pathologies associated with graft rejection or an allergic or autoimmune reaction.
TECHNOLOGICAL BACKGROUND OF THE INVENTION
In the last twelve years, controlled studies have described desensitization based on the oral administration of allergens (1). This method is based on the fact that the oral administration of an antigen facilitates the acquisition of an immunological tolerance to it. The digestive route constitutes the mode of contact of the body with antigens, of food or microbial origin. However, allergic reactions are rare. Oral administration of sheep red blood cells (SRBC) to rats prevents the rats from later producing anti-SRBC antibodies after a subcutaneous injection, whereas, without the prior oral intake, the allergic response would have been present. This phenomenon constitutes what is referred to immunologically as oral tolerance.
This oral desensitization method has been validated in prospective and controlled studies, and makes it possible to reduce the risks of anaphylaxis, in particular for birch pollen and acari. It is already available on the vaccines market in a presentation in drinkable form (sold by the company Laboratoire des Stallergènes—Paris).
Moreover, it may be considered that the benefit, in terms of protecting infants against allergy to milk, which has been observed since the introduction of new, enzymatically predigested powdered milk formulations, would result from the induction of immunological tolerances by the presentation of antigens in the form of peptides.
However, it is difficult to predict or state the efficacy of the desensitization. Clinical observation makes it possible, after the event, to confirm or deny any improvement in the symptoms.
It is known, from international patent application WO 96/36880, to be able to detect and/or quantify ligands specific to a pathology associated with an allergic or autoimmune response or lung cancer, by means of a test of competition between ligands present in a sample and other discriminable ligands. This test is based on the fact that allergic and symptomatic individuals recognize, by means of their antibodies, epitopes different from those recognized by the antibodies of tolerant individuals on the same specific antigenic structure of said pathology. That document also describes the possibility of measuring the evolution of this specificity, in particular in the case of children who are allergic to milk and the change toward the in vivo acquisition of tolerance to milk.
AIMS OF THE INVENTION
The aim of the present invention is to provide a novel composition, which may be of pharmaceutical or food type, designed to modify the immune response of patients toward a pathology associated with an allergic or autoimmune reaction or toward graft rejection phenomena, such that the immune response of said patients comes close to the natural tolerance manifested by normal individuals (who remain free of symptoms although they are also liable to be exposed to this pathology).
The present invention is also directed toward providing an inexpensive pharmaceutical or food composition which is easy to administer and which can be used in a prophylactic and/or therapeutic manner.
CHARACTERISTIC ELEMENTS OF THE INVENTION
The present invention relates to a pharmaceutical or food composition comprising an adequate pharmaceutical or food vehicle, a stress protein (also known as “heat shock protein” or HSP) and at least one of the epitopes (conformational or sequential epitope) of an antigenic structure, said antigenic structure inducing graft rejection, an allergic reaction or an autoimmune reaction. Preferably, the pharmaceutical or food vehicle of the composition is adequate for mucosal (in particular oral) or cutaneous administration.
Advantageously, the stress protein and the epitope form a complex naturally (i.e. without formation of a covalent bond), as described by Roamn et al., Febs (1994), Fouri et al., The Journal of Biological Chemistry, Volume 269 No. 48, pp. 30470-30478 (1994), Palleros et al., The Journal of Biological Chemistry, Volume 269 No. 48, pp. 13107-13114 (1994), Grageroov and Gottesman, Journal of Molecular Biology, No. 241, pp. 133-135 (1994), and Schmid et al., Science, Volume 260, p. 1991 (1994) incorporated below by way of reference.
According to the invention, the epitope (also known as the antigenic determinant) is obtained by a hydrolysis, preferably an enzymatic hydrolysis, in particular with pepsin, of said antigenic structure.
Advantageously, the stress protein is a bacterial stress protein present, for example, in saprophytic bacteria such as
E. coli.
Among the stress proteins of the present invention, mention may be made of the stress protein GroEL, the stress proteins GrpE, DnaK or DnaJ as described in particular by Hendrick and Hartl (Annual Review of Biochemistry, No. 62, p. 349 (1993)) or the heat shock proteins HSP 60, 70, etc.
The expression “phenomenon of graft rejection or allergic or autoimmune reaction” means hypersensitivity reactions of immediate or delayed type brought about by contact in particular with an allergen (this reaction can be immediate and specific (anaphylaxis, urticaria, etc.) or delayed over time) or autoimmune diseases and disorders of the immune system of immediate or delayed type associated with graft rejections of host against graft type and graft against host type.
Autoimmunity is a state of immunization of an individual against his or her own constituents, and the phenomenon of graft rejection is a state of immunization of an individual against foreign constituents (bodily fluids such as blood, cerebrospinal fluid, etc., cells, tissues, organs, antibodies, etc.) deliberately implanted into the patient. These phenomena are observed in particular in pathologies chosen from the group consisting of infections associated with SLE (Systemic Lupus Erythematosus disease), Gougerot-Sjögren syndrome (or Sjögren's disease) and rheumatoid polyarthritis, as well as pathologies such as sarcoidosis and osteopenia, spondylarthritis, scleroderma, multiple sclerosis, amyotrophic lateral sclerosis, hyperthyroidism, Addison's disease, autoimmune hemolytic anemia, Crohn's disease, Goddpasture's syndrome, Graves' disease, Hashimoto's thyroiditis, idiopathic purpural hemorrhage, insulin-dependent diabetes, myasthenia, pemphigus vulgaris, pernicious anemia, poststreptococcal glomerulonephritis, psoriasis and spontaneous sterility, as well as immediate or delayed phenomena observed during graft rejections.
The expression “antigenic structure which induces graft rejection or an allergic or autoimmune reaction” means allergens, preferably chosen from the group consisting of the major allergic antigens present in foods such as eggs, soya and milk, in particular bovine beta-lactoglobulin (BLG) from cow's milk, the major allergic antigens present in plants, molds, medicines (in particular antibiotics) and pollens, the major allergic antigens present in animals, in particular in hairs, and venom, in particular wasp venom, the major antigens of the allergic reaction to acari, to the mite present in house dust (antigen P1
Dermatophagoides pteronyssinus
), the major antigen of
Aspergillus fumagatus
, and staphylococcal enterotoxin B (SEB).
Other non-limiting examples of allergens or mixtures of allergens have also been described in the publication ISBN-91-970475-5-4 by Pharmacia AB, which is incorporated herein by way of reference.
The “antigenic structure” can also be an antigenic complex which induces an autoimmune disease. Preferably, this antigenic structure is specific to lupus (SLE) or Sjögren's disease, in particular the plasma membrane or a portion of this membrane containing membrane DNA with a weight of greater than 100 KD, in particular as described in patent application WO 96/13723, the publication number of 20 which is incorporated by way of reference.
Other non-limiting examples of antigenic complexes
Duchateau Jean
Servais Genevieve
Di Nola-Baron Liliana
Merchant & Gould P.C.
Page Thurman K.
Universite Libre De Bruxelles
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