Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-05-27
1998-10-06
Feisee, Lila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 8, 514885, 530300, 530324, 530327, 5303879, 5303882, 53038822, 5303884, 5303887, 53038873, 53038875, 4241391, 4241431, 4241441, 4241501, 4241531, 4241541, 4241731, A61K 3800, A61K 39395, C07K 1400, C07K 1618
Patent
active
058176179
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The seminal discovery of this invention is that there is structural and functional homology between two proteins from Bordetella pertussis (BP) and a family of eukaryotic proteins called selectins. This homology gives rise to two of the more important aspects of the invention. First, these BP proteins, called pertussis toxin (PT) subunits S2 and S3, and segments of these products can act as analogs of the selectins. Secondly, antibodies to S2 and S3, or segments thereof, can block the functions of selectins.
BP is the Gram-negative prokaryotic bacillus responsible for pertussis or (1906)!. It has been extensively studied and its mode of action is quite well understood. Several vaccines have been proposed based upon the complete organism or purified proteins derived from it. None are completely satisfactory.
During the course of a whooping cough infection, BP attaches specifically to the ciliated epithelium and produces systemic disease by elaborating several toxins, one of which is PT. PT is a major virulence determinant which induces metabolic changes such as hypoglycemia and increased vascular permeability.
PT is a hexameric protein with an A-B (Active-Binding) architecture. The A promoter of PT is composed of a single subunit carrying the catalytically active ADP-ribosylating site. The B oligomer contains the cellular recognition domains and is a complex pentamer containing subunits S2, S3, S4 and S5 in the molar ratio 1:1:2:1 and with molecular weights 21,925; Natl. Acad. Sci. 79, 3129-3133 (1982)!. S2 and S3 exhibit about 80% homology at the level of nucleotide sequence of the genes. In addition to binding the toxin to its target eukaryotic cells, these subunits also mediate the adhesion of BP to ciliated cells and leukocytes because of their ability to bind to eukaryotic carbohydrates.
The genes that code for S2 and S3 have been cloned and sequenced and the Locht and Keith, Science, 232:1258, (1986); Nicosia et al, Proc Natl Acad Sci 83:4631, (1986)!. Recombinant proteins can be purified from inclusion bodies isolated from expression systems, for instance in E. coli. Subcloning and mutation of the subunits by the technique has been accomplished to produce analogs and segments of S2 and S3. Burnette, N., et al (1988) Biotechnology 6,699-706; Burnette, N., et al J. (1988 Science 242,72-74; Cieplak, W., Burnette, et al, J. (1988) Proc. Natl. Acad. Sci. U.S. A. 85,4667-4671.
Selectins (or LEC-CAMs) are a family of cell adhesion molecules that have been implicated in the interaction of leukocytes with platelets or vascular endothelium. Adhesion is a prerequisite for diapedesis of leukocytes through endothelium, and is also necessary for leukocytes homing, a process in which leukocytes exit the blood stream at specific 63:861-3, (1990)!. Selectins recognize carbohydrates for example carbohydrate receptors on leukocytes. Members of the selectin family include ELAM (Endothelial Leukocyte Adhesion Molecule), hLHR (human Lymphocyte Homing Receptor), and GmP 140 (Granual Membrane Protein). ELAM is located on the endothelial cell and is synthesized by the cells in response to inflammatory agents. Interference with its functions prevents leukocyte adhesion to endothelium. hLHR is located on lymphocytes. Interference with its function prevents the normal homing of these cells to lymphoid tissue (e.g. lymph note, Peyer's patches, bronchial lymphoid tissue). GMP 140 is expressed by endothelial cells and platelets and, in a manner not as yet understood, promotes leukocyte adhesion to endothelium and platelets.
SUMMARY OF THE INVENTION
This invention is based on the discovery that there is structural and functional homology between PT, more specifically subunits S2 and S3 of PT, and the selectins ELAM, GMP 140, and hLHR. This is the first recognition of such homology between proteins from prokaryotic and eukaryotic cells. Thus PT, the B oligomer of PT its subunits S2 and S3 and segments thereof can act as analogs of these selecting. Of equal significance is the fact that antibodies to t
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Masure H. Robert
Tuomanen Elaine
Feisee Lila
Gambel Phillip
The Rockefeller University
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