Phosphatidyl serine receptors and uses thereof

Details Phosphatidyl serine receptors and uses thereof Phosphatidyl serine receptors and uses thereof

2001-03-08

2003-10-07

Kunz, Gary (Department: 1647)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving antigen-antibody binding, specific binding protein...

C435S007200, C514S002600, C514S012200, C530S300000, C530S350000

Reexamination Certificate

active

06630313

ABSTRACT:

FIELD OF THE INVENTION
The present invention generally relates to a novel phosphatidylserine (PS) receptor, to homologues thereof, to nucleic acids encoding such a receptor and homologues thereof, to agonist and antagonist compounds that specifically associate with and affect the activation state of such a receptor, including antibodies, antibody fragments and binding partners that selectively bind to such a receptor, and to methods of making and using such a receptor, homologues thereof, and agonist and antagonist compounds of such a receptor.
BACKGROUND OF THE INVENTION
The culmination of apoptosis in vivo is phagocytosis of cellular corpses. Of the numerous cells reported to recognize and remove apoptotic bodies, the macrophage is the most prominent. Apoptotic cells express cell surface changes which allow recognition and removal by macrophages. Removal occurs before lysis, which prevents the release of potentially toxic and immunogenic intracellular contents from the apoptotic cells into the surrounding tissue. Thus, in tissues such as the thymus in which apoptosis is ongoing, normal structure and function are maintained and inflammation is avoided. The removal of apoptotic cells also appears to be critical in the resolution of inflammation. Phagocytosis of apoptotic cells in inflammatory sites has been documented in vivo in experimental as well as clinical disease states, and disorders of apoptosis have been suggested to contribute to the persistence of chronic inflammatory conditions in the lung, kidney and other organs (Grigg et al.,
Lancet.
338:720-722, 1991; Cox et al.,
Am. J. Respir. Cell. Mol. Biol.
12:232-237, 1995; Haslett et al.,
Phil. Trans. R. Soc. Lond. B.
345:327-333, 1994).
During apoptosis, plasma membrane phospholipid asymmetry is lost, exposing phosphatidylserine (PS) externally (Fadok et al.,
J Immunol
148:2207-2216 (1992); Martin et al.,
J Exp Med
182:1545-1556 (1995); Verhoven et al.,
J Exp Med
182:1597-1601 (1995); van den Eijnde et al.,
Apoptosis
3:9-16 (1998)). Phagocytosis of apoptotic cells can be inhibited stereospecifically by PS and its structural analogues, but not by other anionic phospholipids, suggesting that PS is specifically recognized (Fadok et al., ibid.; Fadok et al.,
J Immunol
149:4029-4035 (1992); Fadok et al.,
J Immunol
151:4274-4285 (1993); Fadok et al.,
J Immunol
161:6250-6257 (1998); Pradhan et al.,
Mol Biol Cell
8:767-778 (1997); Bennett et al.,
Circ Res
77:1136-1142 (1995); Shiratsuchi et al.,
J Biol Chem
272:2354-2358 (1997)). However, prior to the present invention, the molecule responsible for PS recognition had not been positively identified.
Several potential candidates for PS recognition on apoptotic cells have been put forth, including CD36, CD68, CD14, and LOX-1 (Savill et al.,
J Clin Invest
90:1513-1522 (1992); Sambrano et al.,
Proc Natl Acad Sci U S A
92:1396-1400 (1995); Devitt et al.,
Nature
392:505-509 (1998); Oka et al.,
Proc Natl Acad Sci U S A
95:9535-9540 (1998)). In addition, &bgr;2GP1 may enhance uptake by bridging PS on the apoptotic cell to receptors on macrophages (Balasubramanian et al.,
J Biol Chem
272:31113-31117 (1997)). However, several observations suggest that receptors other than these scavenger/pattern recognition molecules must exist. These molecules do not appear to discriminate between PS and other anionic phospholipids including phosphatidylinositol (PI) (Oka et al.,
Proc Natl Acad Sci U S A
95:9535-9540 (1998); Rigotti et al.,
J Biol Chem
270:16221-16224 (1995); Wang et al.,
J Biol Chem
273:24309-24313 (1998); Ryeom et al.,
J Cell Sci
109:387-395 (1996); Shiratsuchi et al.,
J Biol Chem
274:5901-5908 (1999)), whereas uptake of apoptotic cells by PS-recognizing macrophages was not blocked by phosphatidylinositol (PI) or other anionic phospholipids (Fadok et al.,
J Immunol
148:2207-2216 (1992); Fadok et al.,
J Immunol
161:6250-6257 (1998)).
The removal of apoptotic cells is critical to normal tissue structure and function. In addition, one of the critical functions of the apoptotic cell when phagocytosed is to actively suppress macrophage proinflammatory functions. The nature and duration of the inflammatory response is determined to a large extent by competition between proinflammatory and anti-inflammatory uptake mechanisms. Disorders in either uptake or response to apoptotic cells by macrophages could contribute to chronic inflammation. Moreover, without being bound by theory, the present inventors believe that some pathogenic microorganisms and viruses may use the phosphatidylserine recognition pathway to gain entrance to a host cell. Also without being bound by theory, phosphatidylserine recognition may play a role in the ability of a tumor cell to avoid an immune response. Therefore, the ability to control cellular interactions which are mediated by phosphatidylserine recognition has multiple therapeutic benefits. Thus, there is a need in the art to identify and characterize the phosphatidylserine receptor.
SUMMARY OF THE INVENTION
The present invention generally relates to isolated phosphatidylserine receptor proteins, nucleic acid molecules, homologues thereof, agonist and antagonist compounds that specifically associate with and affect the activation state of such a receptor, and methods of making and using such a receptor, homologues thereof, and agonist and antagonist compounds of such a receptor.
One embodiment of the present invention relates to an isolated phosphatidylserine receptor protein selected from the group of: (a) a protein consisting essentially an amino acid sequence selected from the group consisting of: (i) an amino acid sequence spanning from between about positions 252 and 289 of SEQ ID NO:3 to about position 414 of SEQ ID NO:3; (ii) an amino acid sequence spanning from between about positions 252 and 289 of SEQ ID NO:5 to about position 403 of SEQ ID NO:5; (iii) an amino acid sequence spanning from between about positions 206 and 243 of SEQ ID NO:7 to about position 349 of SEQ ID NO:7; (iv) an amino acid sequence spanning from between about positions 257 and 294 of SEQ ID NO:9 to about position 408 of SEQ ID NO:9; and, (b) a homologue of the protein of (a), wherein the homologue consists essentially of an amino acid sequence that is at least about 70% identical, and more preferably at least about 80% identical, and more preferably at least about 90% identical, to the amino acid sequence of (a). The isolated phosphatidylserine receptor protein has a phosphatidylserine receptor biological activity. Preferably, such a protein consists essentially of an amino acid sequence selected from the group consisting of: (a) an amino acid sequence spanning from between about positions 289 of SEQ ID NO:3 to position 414 of SEQ ID NO:3; (b) an amino acid sequence spanning from between about positions 289 of SEQ ID NO:5 to position 403 of SEQ ID NO:5; (c) an amino acid sequence spanning from between about positions 243 of SEQ ID NO:7 to position 349 of SEQ ID NO:7; and (d) an amino acid sequence spanning from between about positions 294 of SEQ ID NO:9 to position 408 of SEQ ID NO:9. Particularly preferred phosphatidylserine receptor proteins in this embodiment include a protein that consists essentially of an amino acid sequence spanning from between about positions 252 and 289 of SEQ ID NO:3 to about position 414 of SEQ ID NO:3; and a protein that consists essentially of an amino acid sequence spanning from between about positions 252 and 289 of SEQ ID NO:5 to about position 403 of SEQ ID NO:3.
Another embodiment of the present invention relates to an isolated phosphatidylserine receptor protein selected from the group consisting of: (a) a protein comprising an amino acid sequence selected from the group consisting of SEQ ID NO:5, SEQ ID NO:7, and SEQ ID NO:9; and (b) a homologue of the protein of (a), wherein the homologue comprises an amino acid sequence that is at least 316 amino acid residues in length and that is at least about 70% identical, and more preferably at least about 80% identical, and more preferably at least about

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