Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-11-16
2004-11-16
Housel, James (Department: 1648)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S326000, C530S327000, C530S328000, C530S329000, C530S330000, C530S350000, C435S235100, C435S236000
Reexamination Certificate
active
06818612
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the discovery of methods and compositions for the inhibition of cell growth and migration. More specifically, B19 parvovirus capsids or fragments of B19 parvovirus capsid proteins are incorporated into medicaments that can be administered to a subject to inhibit the growth and/or migration of cells that have a receptor that interacts with a parvovirus B19 capsid or fragment thereof (e.g., a P antigen containing cell), including, but not limited to, cells of hematopoietic origin and endothelial cells.
BACKGROUND OF THE INVENTION
The B19 parvovirus is a human pathogen that can be associated with various clinical conditions, ranging from mild symptoms (erythema infectiosum) to more serious diseases in persons who are immunocompromised or suffer from hemolytic anemias. Hydrops fetalis and intrauterine fetal death are well-known complications of B19 parvovirus infection during pregnancy. (Anderson and Young,
Monographs in Virology,
20 (1997)). The B19 parvovirus particles have icosohedral symmetry, a diameter of 18 to 26 nm, and are composed of 60 capsid proteins, approximately 95% of which are major capsid proteins (VP2) that have a molecular weight of 58 kd. (Fields et al.,
Virology vol.
2, 3rd edition, Lipponcott-Raven Publishers, Philidelphia, Pa., p. 2202 (1996)). Approximately, 3-5% of the capsid proteins that compose a B19 parvovirus capsid are called minor capsid proteins (VP1), which have a molecular weight of 83 kd, and differ from VP2 by an additional 227 amino acids at the amino terminus. (Id.).
The B19 parvovirus is extraordinarily tropic for human erythroid cells and cultures of bone marrow. B19 parvovirus binds to human erythroid progenitor cells, for example, and inhibits hematopoietic colony formation by replicating in these cells. (Brown et al.,
Science,
262:114 (1993) and Mortimer et al.,
Nature,
302:426 (1983)). The suppression of hematopoietic cells has also been seen in bone marrow samples from infected individuals, resulting in transient anemia and, in rare case, transient pancytopenia. (Saunders et al.,
Br J Haematol,
63:407 (1986)). Further, B19 parvovirus is known to cause bone marrow suppression in natural and experimental human infections. (Anderson and Young,
Monographs in Virology,
20 (1997)).
The cellular receptor for B19 parvovirus has been identified as globoside or erythrocyte P antigen, a textrahexoceramide. (Fields et al.,
Virology vol.
2, 3rd edition, Lipponcott-Raven Publishers, Philidelphia, Pa., p. 2204 (1996)). The P antigen is found on mature erythrocytes, erythroid progenitors, megakaryocytes, endothelium, kidney cortex, placenta, fetal myocardium (von dem Borne et al.,
Br J Hematol,
63:35 (1986)) and pronormoblasts from fetal liver. (Morey and Flemming,
Br J Haematol,
82:302 (1992)). Individuals who genetically lack the P antigen are not susceptible to B19 parvovirus infection and administration of either excess P antigen or monoclonal antibodies directed to the P antigen can protect erythroid progenitors from infection with B19 parvovirus. (Id.).
Additionally, neutralizing antibodies that recognize several regions of the B19 parvovirus particle have been generated. For example, monoclonal antibodies directed to epitopes of VP2, such as found at amino acids 38-87, 253-272, 309-330, 328-344, 359-382, 449-468, and 491-515, and the unique region of VP1 can neutralize B19 parvovirus. (Fields et al.,
Virology vol.
2, 3rd edition, Lipponcott-Raven Publishers, Philidelphia, Pa., p. 2207 (1996)).
Genetically engineered expression systems for the production of B19 parvovirus antigens have also been developed. (Kajigaya et al.,
Proc Natl Acad Sci USA,
86:7601 (1989); Kajigaya et al.,
Proc Natl Acad Sci USA,
88:4646 (1991); Brown et al.,
J Virol,
65:2702 (1991)). Like the native particles, recombinant B19 parvovirus capsids, produced in a baculovirus system, are composed of both VP1 and VP2 and these capsid proteins self assemble to form virus-like particles (VLPs). (Kajigaya et al.,
Proc Natl Acad Sci USA,
88:4646 (1991)). Electron microscopic analyses of the B19 parvovirus capsids revealed that the VLPs are structurally similar to plasma-derived virions. (Kajigaya et al.,
Proc Natl Acad Sci USA,
88:4646 (1991)). B19 parvovirus VLPs are currently being evaluated as a potential vaccine against B19 parvovirus infection and preliminary results show a good neutralizing response without severe side effects. (Bostic et al,
J. Infect. Dis.,
179:619 (1999). While many are trying to prevent B19 parvovirus infection by administering B19 parvovirus capsids, none have sought to exploit the properties of the B19 parvovirus capsid, B19 parvovirus capsid proteins, or fragments thereof to develop novel medicaments that inhibit cell proliferation or migration.
BRIEF SUMMARY OF THE INVENTION
It has been discovered that the B19 parvovirus capsid, B19 parvovirus capsid proteins, or fragments thereof inhibit the growth and/or migration of cells that have a receptor that interacts with a parvovirus B19 capsid or fragment thereof (e.g., a P antigen containing cell). The data presented herein demonstrate that the B19 parvovirus capsid, B19 parvovirus capsid proteins, and fragments thereof, inhibit hematopoiesis and endothelial cell growth and migration. Accordingly, the compositions described herein can be used to reduce the production of red blood cells, white blood cells, and blood platelets, as well as, inhibit the growth and migration of other cells having a receptor that interacts with a parvovirus B19 capsid or fragment thereof (e.g., a P antigen containing cell), such as endothelial cells. Because many diseases or maladies are associated with an overproduction of cells of hematopoietic origin and/or invasive growth or migration of cells of endothelial origin, the compositions and methods described herein have significant therapeutic and prophylactic utility.
Embodiments of the invention include medicaments comprising, consisting essentially of, or consisting of B19 parvovirus capsid, B19 parvovirus capsid proteins, or fragments thereof, preferably the tripeptide (QQY) and a 10-mer peptide (NKGTQQYTDQ SEQ. ID. NO. 5), which can be administered to subjects in need of an agent that inhibits cell growth and/or migration. The B19 parvovirus capsid proteins and fragments thereof, preferably VP2 capsid proteins and fragments thereof, can be prepared synthetically, using peptide chemistry or genetic engineering, or can be made by cleaving B19 parvovirus capsids, desirably VP2 capsids, with various proteases, for example an endoprotease, which cleaves at a lysine or arginine residue.
The methods of the invention include approaches to manufacture medicaments that can be used to inhibit the growth or migration of cells that have a receptor that interacts with a parvovirus B19 capsid or fragment thereof (e.g., a P antigen containing cell). By one approach, for example, an active ingredient consisting of, consisting essentially of, or comprising empty, noninfectious, recombinant B19 parvovirus capsids, B19 parvovirus capsid proteins, or fragments of B19 parvovirus capsid proteins, preferably the tripeptide (QQY) and a 10-mer peptide (NKGTQQYTDQ SEQ. ID. NO. 5), are incorporated into a medicament with or without a pharmaceutically acceptable carrier or support. The amount of active ingredient can be varied depending on the potency of the inhibition needed and the length of treatment period desired from a single dose.
The medicaments described herein are preferably used to inhibit hematopoietic cell growth, endothelial cell growth, or endothelial cell migration. The medicaments described herein are used, for example, to treat hematological proliferative disorders, angiogenesis, tumorigenesis, or endothelial cell ingrowth into an implanted prosthetic device. Further, the medicaments described herein can be provided to a subject, including a fetus, prior to stem cell transplantation. Accordingly, methods of prevention and/or treatment of diseases or conditions associated with hematopoietic or e
Broliden Kristina
Westgren Magnus
Housel James
Knobbe Martens Olson & Bear
Lucas Zachariah
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