Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Hormone or other secreted growth regulatory factor,...
Reexamination Certificate
2001-10-26
2004-12-07
Andres, Janet (Department: 1646)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Hormone or other secreted growth regulatory factor,...
C514S002600, C530S350000, C530S399000
Reexamination Certificate
active
06827938
ABSTRACT:
BACKGROUND OF THE INVENTION
Renal failure can occur as a complication of trauma, shock, poisoning, acute pancreatitis, septicemia, chronic exposure to certain drugs, poisoning, and other causes. Acute tubular necrosis (ATN), the most common cause of acute renal failure, usually occurs after a period of inadequate blood flow to the peripheral organs. Anoxia or poisoning leads to death of tubular epithelial cells and progression to acute renal failure. Chronic analgesic nephritis, which results from prolonged exposure to combinations of phenacetin, aspirin, and acetominophen, may also be due to necrosis of tubular epithelial cells. See, Robbins et al.,
Basic Pathology
, Third Edition, W. B. Saunders Co., Philadelphia, 1981, 421-456.
Ischemia- and nephrotoxin-induced renal damages are the main causes of acute renal failure and are characterized by structural and functional damages to renal tubular epithelial cells, predominantly to the proximal tubuli (Oliver et al.,
J. Clin. Invest
. 30:1307-1439, 1951). Damage to the proximal tubular epithelium is repaired by a complex regeneration process. After cell desquamation, dedifferentiated proximal tubular cells proliferate and migrate into the denuded area of the basement membrane to establish a new epithelium (Wallin et al.,
Lab Invest
. 66:474-484, 1992). In many respects, this nephrogenic repair process resembles the late stage of the development of nephrons, when the embryonic mesenchyme converts to a tubular epithelium (Wallin et al., ibid.; Hammermann et al.,
A. J. Physiol
. 262:F523-532, 1992).
While a functional tubular epithelium may be regenerated in as little as 2 weeks, the clinical course of ATN is prolonged in many patients, and treatment consists of supportive care, including dialysis. Without adequate treatment, ATN results in death.
There remains a need in the art for compositions and methods for stimulating the proliferation of kidney tubule epithelial cells in vivo, and thereby improving kidney function.
DESCRIPTION OF THE INVENTION
The present invention provides materials and methods for improving kidney function or enhancing proliferation or survival of kidney tubule epithelial cells or epithelial cell precursors in a mammal.
Within one aspect of the invention there is provided a method of improving kidney function in a mammal in need thereof, comprising administering to the mammal a composition comprising a therapeutically effective amount of a zvegf4 protein or a zvegf4 protein-encoding polynucleotide in combination with a pharmaceutically acceptable delivery vehicle.
Within a second aspect of the invention there is provided a method of enhancing proliferation or survival of kidney tubule epithelial cells or epithelial cell precursors in a mammal, comprising administering to the mammal a composition comprising a therapeutically effective amount of a zvegf4 protein or a zvegf4 protein-encoding polynucleotide in combination with a pharmaceutically acceptable delivery vehicle.
Within certain embodiments of the above-disclosed methods, a zvegf4 protein is administered to the mammal. Within selected embodiments, the zvegf4 protein is a disulfide-bonded dimer of two polypeptide chains, each of the chains comprising residues 258-370 of SEQ ID NO:2, residues 250-370 of SEQ ID NO:2, or residues 246-370 of SEQ ID NO:2. Within other embodiments the zvegf4 protein is a disulfide-bonded dimer of two polypeptide chains, each of the chains consisting of residues X to 370 of SEQ ID NO:2, wherein X is an integer from 246 to 258, inclusive, and wherein the protein is optionally glycosylated.
Within other embodiments of the above-disclosed methods, a zvegf4 protein-encoding polynucleotide is administered to the mammal. Within selected embodiments, the polynucleotide encodes a polypeptide comprising residues 258-370 of SEQ ID NO:2, residues 19-370 of SEQ ID NO:2, or residues 1-370 of SEQ ID NO:2. Within other embodiments, the polynucleotide is a viral vector or plasmid.
Within other embodiments of the invention, the zvegf4 protein is a disulfide-bonded dimer of two polypeptide chains, each of the chains consisting of residues x-y of SEQ ID NO:2, inclusive, wherein the protein is optionally glycosylated, and wherein x is selected from the group consisting of 16, 17, 18, 19, 20, 21, 22, 24, 25, 35, 52, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 246, 250, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, and 263; and y is selected from the group consisting of 365, 366, 367, 368, 369, and 370.
Within other embodiments of the above-disclosed methods, the mammal is suffering from acute tubular necrosis.
These and other aspects of the invention will become evident upon reference to the following detailed description of the invention and the accompanying Figure.
The Figure is a Hopp/Woods hydrophilicity profile of the amino acid sequence shown in SEQ ID NO:2. The profile is based on a sliding six-residue window. Buried G, S, and T residues and exposed H, Y, and W residues were ignored. These residues are indicated in the figure by lower case letters.
“Conservative amino acid substitutions” are defined by the BLOSUM62 scoring matrix of Henikoff and Henikoff,
Proc. Natl. Acad. Sci. USA
89:10915-10919, 1992, an amino acid substitution matrix derived from about 2,000 local multiple alignments of protein sequence segments, representing highly conserved regions of more than 500 groups of related proteins. As used herein, the term “conservative amino acid substitution” refers to a substitution represented by a BLOSUM62 value of greater than−1. For example, an amino acid substitution is conservative if the substitution is characterized by a BLOSUM62 value of 0, 1, 2, or 3. Preferred conservative amino acid substitutions are characterized by a BLOSUM62 value of at least 1 (e.g., 1, 2 or 3), while more preferred conservative amino acid substitutions are characterized by a BLOSUM62 value of at least 2 (e.g., 2 or 3).
A “polypeptide” is a polymer of amino acid residues joined by peptide bonds, whether produced naturally or synthetically. Polypeptides of less than about 10 amino acid residues are commonly referred to as “peptides”.
A “protein” is a macromolecule comprising one or more polypeptide chains. A protein may also comprise non-peptidic components, such as carbohydrate groups. Carbohydrates and other non-peptidic substituents may be added to a protein by the cell in which the protein is produced, and will vary with the type of cell. Proteins are defined herein in terms of their amino acid backbone structures; substituents such as carbohydrate groups are generally not specified, but may be present nonetheless. Thus, a protein “consisting of”, for example, from 15 to 1500 amino acid residues may further contain one or more carbohydrate chains.
The terms “treat” and “treatment” are used broadly to denote therapeutic and prophylactic interventions that favorably alter a pathological state, including alleviating symptoms thereof. Treatments include procedures that moderate or reverse the progression of, reduce the severity of, prevent, or cure a disease.
The term “zvegf4 protein” is used herein to denote a protein comprising the growth factor domain of a zvegf4 polypeptide (e.g., residues 258-370 of human zvegf4 (SEQ ID NO:2) or mouse zvegf4 (SEQ ID NO:4)), wherein said protein or a proteolytically activated form thereof is mitogenic for cells expressing cell-surface PDGF &agr;- and/or &bgr;-receptor subunit. Zvegf4 has been found to activate the &agr;&agr;, &agr;&bgr;, and &bgr;&bgr; isoforms of PDGF receptor. Zvegf4 proteins include homodimers and heterodimers as disclosed below. Using methods known in the art, zvegf4 proteins can be prepared in a variety of forms, including glycosylated or non-glycosylated, pegylated or non-pegylated, with or without an initial methionine residue, and as fusion proteins as disclosed in more detail below.
A “zvegf4 protein-encoding polynucleotide” is a polynucleotide that encodes, upon expression by a host cell, a zvegf4 polypeptide that is post-translationally processed to yield a dimeric
Hart Charles E.
Topouzis Stavros
Andres Janet
Parker Gary E.
ZymoGenetics Inc.
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