Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-05-17
2003-02-25
Duffy, Patricia A. (Department: 1645)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S300000
Reexamination Certificate
active
06525018
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is peptides useful for treatment of disorders of the digestive system, disorders of the eye and disorders associated with unwanted apoptosis.
BACKGROUND
Jørgensen et al. (1982,
Regulatory Peptides
3:231) describe a porcine pancreatic peptide, pancreatic spasmolytic peptide (PSP). PSP was found to inhibit “gastrointestinal motility and gastric acid secretion in laboratory animal after parenteral as well as oral administration.” It was suggested that “if the results in animal experiments can be confirmed in man, PSP may possess a potential utility in treatment of gastroduodenal ulcer diseases.”
pS2 is a small cysteine-rich protein which is expressed and secreted from human breast tumours. In addition, pS2 protein is expressed in normal stomach mucosa and in regenerative tissues in ulcerative diseases of the gastrointestinal tract (Rio et al.,
Cancer Cells,
1990, 2:269-74).
SUMMARY OF THE INVENTION
In a first aspect, the invention features a purified nucleic acid encoding an intestinal trefoil factor (ITF).
In preferred embodiments, the ITF is a mammalian ITF, preferably human, rat, bovine, mouse, monkey or porcine ITF. In another preferred embodiment, the purified nucleic acid encoding an ITF is present within a vector. In one embodiment, the ITF is in a monomer form. In another embodiment, two monomer ITF can be linked by a disulfide bond to form a dimer.
In a related aspect, the invention features a cell that includes a vector encoding an ITF.
In another related aspect, the invention features a substantially pure ITF. In a preferred embodiment, the polypeptide is detectably labelled. In a related aspect, the invention features a therapeutic composition that includes an ITF and a pharmacologically acceptable carrier.
In another aspect the invention features ITF variants.
In another aspect, the invention features a monoclonal antibody which preferentially binds (i.e., forms an immune complex with) an ITF. In a preferred embodiment, the monoclonal antibody is detectably labelled.
In a related aspect, the invention features a method for detecting human ITF in a human patient. The method includes the steps of contacting a biological sample obtained from the patient with a monoclonal antibody which preferentially binds ITF, and detecting immune complexes formed with the monoclonal antibody. In preferred embodiments the biological sample is an intestinal mucosal scraping, or serum.
In a related aspect, the invention features a method for treating digestive disorders in a human patient, which method involves administering to the patient a therapeutic composition that includes an ITF and a pharmacologically acceptable carrier. In one embodiment, a wild-type ITF protein, e.g., a human ITF protein (
FIG. 6
, SEQ ID NO:4), is used to treat a digestive disorder. A wild-type ITF protein is resistant to destruction in the digestive tract, and can be used for treatment of a digestive disorder such as a peptic ulcer disease, an inflammatory bowel disease, and can be used to protect the intestinal tract from injury caused by insults such as radiation injury or bacterial infection.
In another related aspect, the invention features a method for treating an eye disorder in a human patient, which method involves administering to the patient a therapeutic composition that includes an ITF protein and a pharmacologically acceptable carrier. An ITF protein and biologically active fragments or variants thereof can be used for the treatment of eye disorders such as a corneal ulcer, or an ocular inflammatory disease. An ITF and biologically active fragments or variants thereof can be used to treat corneal injury or lesion associated with corneal transplantation, lens implantation and other types of eye surgery. ITF can also be used to treat traumatic physical injury to the eye. The methods of the invention also include treating eye disorders with SP or pS2 protein, e.g., a human Sp or pS2 protein (
FIG. 9
, SEQ ID NO:14 and
FIG. 10
, SEQ ID NO:16), respectively. In addition, biologically active fragments or variants of SP or pS2 can be used to treat eye disorders. Any or all of the trefoil proteins can be administered to treat an eye disorder (see Sands, Annual Rev. Physiol 58:253-73). ITF or pS2 can be administered in monomer form or can be administered in a dimer form.
In yet another related aspect, the invention features a method for modulating apoptosis in a human patient, which method involves administering to the patient a therapeutic composition that modulates expression or activity of ITF and a pharmacologically acceptable carrier. The methods of the invention also include a method of modulating apoptosis by administering a therapeutic composition that modulates expression or activity of SP or pS2. In addition, biologically active fragments or variants of SP or pS2 can be used to modulate apoptotic disorders. Any or all of the trefoil proteins can be administered. ITF or pS2 can be administered in monomer form or can be administered in a dimer form.
In another aspect, the invention features a method for detecting binding sites for ITF in a patient. The method involves contacting a biological sample obtained from the patient with the factor, and detecting the factor bound to the biological sample as an indication of the presence of the binding sites in the sample. By “binding sites,” as used herein, is meant any antibody or receptor that binds to an ITF protein, factor, or analog. The detection or quantitation of binding sites may be a useful reflection of abnormalities of the digestive tract.
In another aspect, the invention features substantially pure ITF. In preferred embodiments, the ITF is human, porcine, mouse, rat, guinea pig, monkey, or bovine trefoil factor.
By “intestinal trefoil factor” (“ITF”) is meant any protein that is substantially homologous to rat ITF (
FIG. 2
, SEQ ID NO.:2) or human ITF (
FIG. 6
, SEQ ID NO:4) and which is expressed in the large intestine, small intestine, or colon to a greater extent than it is expressed in tissues other than the small intestine, large intestine, or colon. Also included are: allelic variations; natural mutants; induced mutants; proteins encoded by DNA that hybridizes under high or low stringency conditions to ITF encoding nucleic acids retrieved from naturally occurring material; and polypeptides or proteins retrieved by antisera to ITF, especially by antisera to the active site or binding domain of ITF. The term also includes other chimeric polypeptides that include an ITF.
The term ITF also includes analogs of naturally occurring ITF polypeptides. Analogs can differ from the naturally occurring ITF by amino acid sequence differences or by modifications that do not affect sequence, or by both. Analogs of the invention will generally exhibit at least 70%, more preferably 80%, more preferably 90%, and most preferably 95% or even 99%, homology with all or part of a naturally occurring ITF sequence. The length of comparison sequences will generally be at least 8 amino acid residues, usually at least 20 amino acid residues, more usually at least 24 amino acid residues, typically at least 28 amino acid residues, and preferably more than 35 amino acid residues. Modifications include in vivo, or in vitro chemical derivatization of polypeptides, e.g., acetylation, or carboxylation. Also included are modifications of glycosylation, e.g., those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps, e.g., by exposing the polypeptide to enzymes that affect glycosylation derived from cells that normally provide such processing, e.g., mammalian glycosylation enzymes. Also embraced are versions of the same primary amino acid sequence that have phosphorylated amino acid residues, e.g., phosphotyrosine, phosphoserine, or phosphothreonine. Analogs can differ from naturally occurring ITF by alterations of their primary sequence. These include genetic variants, both natural and induced. Induced mutants may be derived by various techniq
Clark & Elbing LLP
Duffy Patricia A.
The General Hospital Corp.
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