Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds antigen or epitope whose amino acid sequence is...
Reexamination Certificate
1996-10-16
2004-11-16
Nolan, Patrick J. (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds antigen or epitope whose amino acid sequence is...
C424S152100
Reexamination Certificate
active
06818214
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the psoriastatin type I and II genes, psoriastatin type I; and II polypeptides, and methods of using psoriastatin nucleic acids and polypeptides.
BACKGROUND OF THE INVENTION
Psoriasis is a disease chacterized by abnormal proliferation of keratinocytes and inflammation of the involved skin. A variety of proteinases which are not found in normal epidermis has been reported to appear in such skin.
SUMMARY OF THE INVENTION
In general, the invention features a psoriastatin type I polypeptide, e.g., a polypeptide, the sequence of which includes, or is, all or part of the sequence shown in SEQ ID NO:2. Preferred embodiments include fragments and analogs of SEQ ID NO:2, preferably having at least one biological activity of a psoriastatin type I polypeptide.
In preferred embodiments, the polypeptide is a recombinant or a substantially pure preparation of a psoriastatin type I polypeptide.
In preferred embodiments, the residue at position 357 (according to the numbering system used herein) is: other than alanine; a residue having a side chain group of greater molecular weight from the side chain group of alanine; a basic residue; an acidic residue; a threonine.
In preferred embodiments: the polypeptide has at least one biological activity, e.g., it reacts with an antibody, or antibody fragment, specific for a psoriastatin type I polypeptide; the polypeptide includes an amino acid sequence at least 60%, 80%, 90%, 95%, 98%, or 99% homologous to an amino acid sequence from SEQ ID NO:2; the polypeptide includes an amino acid sequence essentially the same as an amino acid sequence in SEQ ID NO:2; the polypeptide is at least 5, 10, 20, 50, 100, 150, 200, or 250 amino acids in length; the polypeptide includes at least 5, preferably at least 10, more preferably at least 20, most preferably at least 50, 100, 150, 200, or 250 contiguous amino acids from SEQ ID NO:2; the polypeptide is preferably at least 10, but no more than 100, amino acids in length; the psoriastatin type I polypeptide is either, an agonist or an antagonist, of a biological activity of a naturally occurring psoriastatin type I polypeptide.
In preferred embodiments: the psoriastatin type I polypeptide is encoded by the nucleic acid sequence of SEQ ID NO:1, or by a nucleic acid having at least 60%, 70%, 80%, 90%, 95%, 98%, or 99% homology with the nucleic acid of SEQ ID NO:1. For example, the psoriastatin type I polypeptide can be encoded by a nucleic acid sequence which differs from a nucleic acid sequence of SEQ ID NO:1 due to degeneracy in the genetic code.
In a preferred embodiment the psoriastatin type I polypeptide is an agonist of a naturally-occurring mutant or wild type psoriastatin type I polypeptide (e.g., a polypeptide having an amino acid sequence shown in SEQ ID NO:2). In another preferred embodiment, the polypeptide is an antagonist which, for example, inhibits an undesired activity of a naturally-occurring psoriastatin type I polypeptide (e.g., a mutant polypeptide).
In a preferred embodiment, the psoriastatin type I polypeptide differs in amino-acid sequence at 1, 2, 3, 5, 10 or more residues, from a sequence in SEQ ID NO:2. The differences, however, are such that the psoriastatin type I polypeptide exhibits at least one biological activity of a psoriastatin type I polypeptide, e.g., the psoriastatin type I polypeptide retains a biological activity of a naturally occurring psoriastatin type I polypeptide.
In preferred embodiment the psoriastatin type I polypeptide includes a psoriastatin type I polypeptide sequence, as described herein, as well as other N-terminal and/or C-terminal amino acid sequences.
In preferred embodiments, the polypeptide includes all or a fragment of an amino acid sequence from SEQ ID NO:2, fused, in reading frame, to additional amino acid residues, preferably to residues encoded by genomic DNA 5′ to the genomic DNA which encodes a sequence from SEQ ID NO:2.
In yet other preferred embodiments, the psoriastatin type I polypeptide is a recombinant fusion protein having a first psoriastatin type I polypeptide portion and a second polypeptide portion having an amino acid sequence unrelated to a psoriastatin type I polypeptide. The second polypeptide portion can be, e.g., any of glutathione-S-transferase, a DNA binding domain, or a polymerase activating domain. In preferred embodiment the fusion protein can be used in a two-hybrid assay.
In a preferred embodiment, the psoriastatin type I polypeptide is a fragment or analog of a naturally occurring psoriastatin type I polypeptide which inhibits reactivity with antibodies, or F(ab′)
2
fragments, specific for a naturally occurring psoriastatin type I polypeptide.
In a preferred embodiment, the psoriastatin type I polypeptide includes a sequence which is not present in the mature protein.
In a preferred embodiment, the psoriastatin type I polypeptide has a molecular weight of about 43 kDa.
In preferred embodiments, the psoriastatin type I polypeptide has one or more of the following properties: the residue at position 357 is other than alanine: has a molecular weight of about 43 kDa; can be isolated from psoriatic tissue; is expressed in psoriatic tissue. e.g., psoriatic epidermis, at least 2, and preferably at least 5 or 10 times more abundantly than in normal tissue; is a cross-class inhibitor (e.g., it inhibits cysteine proteinases, e.g., cathepsin L. but does not inhibit serine proteinases); inhibits cathepsin L at least 2. more preferably at least 2, 5, 10, or 100 times less efficiently than does squamous cell carcinoma-antigen (SCC-A); inhibits cathepsin L but not cathepsin B or cathepsin H; is active at pH 5.0; is secreted.
Polypeptides of the invention include those which arise as a result of the existence of multiple genes, alternative transcription events, alternative RNA splicing events, and alternative translational and postranslational events.
The invention includes an immunogen which includes an active or inactive psoriastatin type I polypeptide, or an analog or a fragment thereof, in an immunogenic preparation, the immunogen being capable of eliciting an immune response specific for the psoriastatin type I polypeptide, e.g., a humoral response, an antibody response, or a cellular response. In preferred embodiments, the immunogen comprising an antigenic determinant, e.g., a unique determinant, from a protein represented by SEQ ID NO:2.
The invention also includes an antibody preparation, preferably a monoclonal antibody preparation, specifically reactive with an epitope of the psoriastatin type I immunogen or generally of a psoriastatin type I polypeptide.
In another aspect, the invention provides a substantially pure nucleic acid having, or comprising, a nucleotide sequence which encodes a polypeptide, the amino acid sequence of which includes, or is, the sequence of a psoriastatin type I polypeptide, or analog or fragment thereof.
In preferred embodiments, the nucleic acid encodes a polypeptide having one or more of the following characteristics: at least one biological activity of a psoriastatn type I polypeptide, e.g., a polypeptide specifically reactive with an antibody, or antibody fragment, directed against a psoriastatin type I polypeptide; an amino acid sequence at least 60%, 80%, 90%, 95%, 98%, or 99% homologous to an amino acid sequence from SEQ ID NO:2; an amino acid sequence essentially the same as an amino acid sequence in SEQ ID NO:2, the polypeptide is at least 5, 10, 20, 50, 100, 150, 200, or 250 amino acids in length; at least 5, preferably at least 10, more preferably at least 20, most preferably at least 50, 100, 150, 200, or 250 contiguous amino acids from SEQ ID NO:2; an amino acid sequence which is preferably at least 10, but no more than 100, amino acids in length; the ability to act as an agonist or an antagonist of a biological activity of a naturally occurring psoriastatin type I polypeptide.
In preferred embodiments: the nucleic acid is or includes the nucleotide sequence of SEQ ID NO:1; the nucleic acid is at least 60%, 70%, 80%, 90%, 95%, 98%,
Baciu Peter C.
Goetinck Paul F.
Hibino Toshihiko
Takahashi Tadahito
Nolan Patrick J.
The General Hospital Corporation
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