Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Allergen or component thereof
Reexamination Certificate
1995-06-05
2002-01-01
Scheiner, Laurie (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Allergen or component thereof
C424S185100, C424S276100
Reexamination Certificate
active
06335019
ABSTRACT:
DESCRIPTION
FUNDING
Work described herein was supported by the National Institutes of Health (Grant No. AI14908).
BACKGROUND OF THE INVENTION
Genetically predisposed individuals, who make up about 10% of the population, become hypersensitized (allergic) to antigens from a variety of environmental sources to which they are exposed. Those antigens that can induce immediate and/or delayed types of hypersensitivity in people are called allergen. King, T. P.,
Adv. Immun.
, 23:77-105 (1976). Anaphylaxis or atopy, which includes the symptoms of hay fever, asthma and hives, is one form of immediate allergy. It can be caused by a variety of atopic allergens, such as products of grasses, trees, weeds, animal dander, insects, and food, drugs and chemicals.
The antibodies involved in atopic allergy belong primarily to the IgE class of immunoglobulins. IgE binds to mast cells and basophils. Upon combination of a specific allergen with IgE bound to mast cells, the IgE is cross-linked on the cell surface, resulting in the physiological effects of IgE-antigen interaction. Degranulation results in release of, among other substances, histamine, heparin, a chemotactic factor for eosinophilic leukocytes and the leukotrienes, C4, D4 and E4, which cause prolonged constriction of bronchial smooth muscle cells. Hood, L. E. et al.,
Immunology
, (2nd ed.), pp460-462, The Benjamin/Cumming Publishing Co., Inc. (1984). These released substances are the mediators which result in allergic symptoms caused by combination of IgE with a specific allergen. Through them, the effects of an allergen are manifested. Such effects may be systemic or local in nature, depending on the route by which the antigen entered the body and the pattern of deposition of IgE and mast cells. Local manifestations generally occur on epithelial surfaces at the location at which the allergen entered the body. Systemic effects can include anaphylaxis (anaphylactic shock), which is the result of an IgE-basophil response to circulating (intravascular) antigen.
One allergen of particular concern for many people is Antigen or
Amb a
I, a poorly-defined constituent (or group of constituents) which is the major allergenic component(s) of short ragweed (
Ambrosia artemisiifolia I
. or
Ambrosia elatior
) pollen and the major cause of late summer hayfever in North America and Canada. Smith, J. J., et al.,
Mol. Immun
, 25:355-364 (1988); King, T. P., et al.,
Biochem.
, 3:458-468 (1964); King, T. P.,
Adv. Immun.
, 23:77-105 (1976). It has been estimated that, on average, as much as 13% of the total serum IgE in ragweed-sensitive individuals is specific for
Amb a
I. Zeiss, C. R., et al.,
J. Immun.
, 110:414-421 (1973).
Amb a
I has been claimed to be an acidic, 38,000 molecular weight, non-glycosylated protein which is cleaved during extraction and chromatographic isolation into two non-covalently associated chains: an alpha chain of 26,000 molecular weight and a beta chain of 12,000 molecular weight. Knox, R. B., et al.,
Nature
, 255:1066-1068 (1970); Knox, R. B., and Heslop-Harrison, J.,
J. Cell Sci.
, 6:1-27 (1970); King, T. P.,
Adv. Immun.
, 23:77-105 (1976); King, T. P., et al.,
Archs Biochem. Biophys.
, 212:127-135 (1981). The two-chain and the single chain forms of
Amb a
I, which are both highly reactive with IgE, are allergenically and antigenically related. King, T. P., et al.,
Biochemistry
, 3:458-468 (1964). It has been shown, however, that several physical and chemical modifications of
Amb a
I cause a marked loss of antigen and allergenic activity. King, T. P., et al.,
Archs Biochem. Biophys.
, 212:127-135 (1981); King, T. P., et al.,
Immunochemistry
, 11: 83-92 (1974).
Because ragweed pollen is the chief causative agent of late-summer hay fever in the eastern United States and Canada, it has been the subject of more studies by different laboratories than any other pollen allergen. King, T. P.,
Adv. Immun.
, 23:77-105 (1976). Despite extensive study, the immunochemical definition of
Amb a
I is still far from complete. Smith and co-workers have begun characterization of the epitope structure of
Amb a
I, using a series of murine monoclonal antibodies raised against purified, native
Amb a
I. Three non-overlapping, non-repeating antigenic sites were defined (sites A, B, and C) and monoclonal antibodies directed to sites A and B together resulted in inhibition of 80% of human IgE binding to
Amb a
I. The reactivity of the monoclonal antibodies used was greatly diminished when
Amb a
I was physically or chemically modified. Olsen, Ph.D. thesis, University of North Carolina, Chapel Hill (1986); Olson, J. R., and Klapper, D. G.,
J. Immun.
, 136:2109-2115 (1986). They indicated that the two sites (A and B) are conformationally dependent epitopes. That is, they are either single structures which lose their conformation during modification or composite structures made up of two or more discontinuous peptides which are proximal in the native allergen but separate once the allergen has been modified. Smith, J. J., et al.,
Mol. Immun.
, 25:355-364 (1988).
Despite the considerable attention ragweed allergens have received, definition or characterization of the structure(s) or component(s) of the allergen responsible for its adverse effects on people is far from complete and current desentization therapy involves treatment with a complex, ill-defined extract of ragweed pollen.
SUMMARY OF THE INVENTION
The present invention relates to allergenic proteins or peptides from ragweed, DNAs encoding all or a portion of such allergenic proteins or peptides; to compositions containing such an allergen(s) or portions of the allergen(s); and to methods of administering the allergen(s) or a portion thereof or a composition which includes the allergen(s) or portions thereof to reduce or prevent the adverse effects that exposure to the allergen normally has on ragweed-sensitive individuals (i.e., to desensitize individuals to the allergen or block the effects of the allergen). The present invention further relates to methods of diagnosing sensitivity to ragweed pollen.
It has now been shown that Antigen E or
Amb a
I is not a single protein but, rather, a family or families of proteins to which ragweed-sensitive individuals react. In particular, the present invention relates to DNA encoding an amino acid sequence or peptide present in allergenic proteins from ragweed pollen. It relates to DNA encoding all or a portion of the ragweed allergen
Amb a
I or Antigen E preparation which has been isolated. Such ragweed allergen preparations are heterogeneous in nature and may include, in additions to what is currently referred to as
Amb a
I or Antigen E, other ragweed components which are allergenic (i.e., cause the typical adverse effects observed in a ragweed-sensitive individual upon exposure to ragweed pollen). These may include, for example, what is referred to in the literature as Antigen K and referred to herein as
Amb a
II. The present invention also relates to DNAs encoding similar amino acid sequences (i.e., DNA encoding amino acid sequences of allergens) in types of ragweed other than short ragweed, such as giant ragweed and western ragweed.
REFERENCES:
patent: 4338297 (1982-07-01), Michael et al.
patent: 90/11293 (1990-10-01), None
Hurtenbach et al J Exp Medicine vol. 177 1499-1504, 1993.*
Ashton-Rickardt et al Cell vol. 76 651-663, Feb. 1994.*
Livingstone el at Ann Rev immunol vol. 5 477-501, 1987.*
Goodfriend, L. et al. (1985) “RA-5G A Homologue of RA-5 in Giant Ragweed Ambrosia-trifida pollen isolation Hla-dr-associated activity and amino-acid sequence” Molecular Immunology 22(8):899-906.
Ishizeka, K. et al. (1975)J. of Immunology114(1):110-115.
King, T.P. and P.S. Norman (1962)Biochemistry1(4):709-720.
King, T.P. et al. (1964) Isolation and characterization of allergens from ragweed pollen. II.Biochemistry3(3):458-468.
King, T.P. et al. (1981) “Limited Proteolysis of Antigens E and K from Ragweed Pollen”Arch. Biochem. Biophy.212(1):127-135.
King, T.P. et al. (1974) “Chemical modification of the major allergen of ragw
Klapper David G.
Kuo Mei-chang
Rafnar Thorunn
Rogers Bruce
Immulogic Pharmaceutical Corp.
Lahive & Cockfield LLP
Scheiner Laurie
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