Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 25 or more amino acid residues in defined sequence
Patent
1991-07-15
1993-01-19
Lacey, David L.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
25 or more amino acid residues in defined sequence
53038822, 5303871, 530862, 435 691, 536 2353, 536867, C07K 1300
Patent
active
051808056
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a polypeptide competitor for human Immunoglobulin E (IgE). More particularly the invention relates to a polypeptide which is capable of binding specifically to the high affinity Fc receptor sites for IgE which exist on human cells, particularly on mast cells and basophils, thereby inhibiting the biological responses, such as exocytosis or degranulation, which take place when antigen specific IgE binds to and crosslinks such receptor sites in the presence of antigen. The invention also relates to pharmaceutical preparations in which the polypeptide is an active constituent. The invention further relates to a method for the preparation of the polypeptide using genetically modified bacteria.
In the human immune system, the principal role of IgE is believed to be to provide immunity to parasites. It also, however, mediates Type I hypersensitivity which is an allergic response leading to the manifestation of such symptoms as hay fever and asthma. Briefly, the mechanism of the allergic response is that on encountering a normally innocuous antigen such as pollen, synthesis of antigen-specific IgE by B-cells is initiated. The antigen-specific IgE then binds to mast cell receptor sites via its Fc region and thereafter any further encounter with the antigen triggers degranulation of the mast cells releasing mediators, principally histamine, resulting in the acute inflammatory symptoms typical of Type I hypersensitivity.
Structurally, IgE, in common with the other immunoglobulins, comprises two heavy and two light chains, the epsilon heavy chain having five domains, a variable domain VH and constant domains CH1 to CH4. The molecular weight of IgE is in the region of 188,000 of which the heavy chain accounts for about 72,500, representing a sequence of approximately 550 amino acid residues.
It has been reported (Nature, vol.315, 1985, No.6020, pp 577-578) that a peptide sequence of 330 amino-acids corresponding to amino acid residues 218 to 547 (in accordance with the numbering given by Bennich, Progress in Immunology II, Vol I, July 1974, pp 49-58) of the epsilon heavy chain of IgE has an inhibitory effect on the release of mediators from human mast cells. The numbering is erroneously assigned in that paper in Nature; the more correct numbering would be 208 to 537. The 330 amino-acid sequence exists as a dimer consisting of two chains of amino-acids, each of 330 amino-acids in length, linked by disulphide bonds.
U.S. Pat. Nos. 4,171,299 and 4,161,522 disclose that an oligopeptide containing from three to ten amino acids in a sequence selected from a portion of amino acids 265 to 537 of the Bennich nomenclature (see reference above) of the Fc region of human IgE will block Fc receptors of mast cells thus inhibiting degranulation and release of mediators such as histamine. The most active of these oligopeptides is identified as the pentapeptide Asp-Ser-Asp-Pro-Arg (called HEPP: Human Immunoglobulin E Polypeptide) derived from the amino acid sequence 320 to 324 of the IgE heavy chain. In native IgE amino acid 322 is asparagine, but it is suggested in the Patents that substitution of asparagine by aspartic acid leads to a substantial enhancement of the blocking activity.
In the Patents mentioned above the full sequence which is attributed to Bennich (Progress in Immunology II, Vol I, July 1974, pp 49-58) is quoted and shows aspartic acid at location 322. However, Bennich himself later asserts (Int. Arch. Allergy Appl. Immunol. 53, 459) that asparagine resides at that location. Bennich also reports that neither of the peptides Asp-Ser-Asp-Pro-Arg nor Asp-Ser-Asn-Pro-Arg has any blocking activity. Determination of the gene sequence has shown that amino acid 322 is asparagine and not aspartic acid. In European Patent Application No. 102634 asparagine and not aspartic acid is correctly quoted at the equivalent location.
Further, it is also reported that the specific activity of HEPP is low requiring excessively large doses for any significant physiological effect.
It is knwon that IgE epsilon chain
REFERENCES:
patent: 4161522 (1979-07-01), Hamburger
patent: 4171299 (1979-10-01), Hamburger
Geha et al. (1985) "Inhibition of the Prausnitz-Kustner reaction by an immunoglobulin -chain fragment synthesized in E. coli."Nature (London) 315: 577-578.
Bennich et al. (1977) "Failure of the putative IgE pentapeptide to compete with IgE for receptors on basophils and mast cells." Int. Archs. Allergy Appl. Immun. 53: 459-468.
Gergely et al. (1984) "Localization of IgG Fc fragment epitopes which are responsible for antibody-dependent cellular cytotoxicity." Soviet immunology 5: 39-43.
Conrad et al, J. of Immunology 132(2): 796-803 (1984).
Gould Hannah J.
Helm Birgit A.
Guest Shelly J.
Lacey David L.
Research Corporation Limited
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