Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2000-03-17
2003-06-10
Nolan, Patrick J. (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C435S326000, C530S387100, C530S388100, C530S388260
Reexamination Certificate
active
06576745
ABSTRACT:
This invention relates, in part, to newly identified polynucleotides and polypeptides; variants and derivatives of the polynucleotides and polypeptides, processes for making the polynucleotides and the polypeptides, and their variants and derivatives, agonists and antagonists of the polypeptides; and uses of the polynucleotides, polypeptides, variants, derivatives, agonists and antagonists. In particular, in these and in other regards, the invention relates to polynucleotides and polypeptides of human Cystatin F.
This invention relates, in part, to newly identified polynucleotides and polypeptides; variants and derivatives of the polynucleotides and polypeptides; processes for making the polynucleotides and the polypeptides, and their variants and derivatives; agonists and antagonists of the polypeptides; and uses of the polynucleotides, polypeptides, variants, derivatives, agonists and antagonists. In particular, in these and in other regards, the invention relates to polynucleotides and polypeptides of human Cystatin F.
BACKGROUND OF THE INVENTION
The cystatin superfamily comprises a group of cysteine proteinase inhibitors which are widely distributed in human tissues and body fluids, and which form tight and reversible complexes with cysteine proteinases such as cathepsins B, H, L, and S. The cystatins are most likely involved in the regulation of normal or pathological processes in which these proteinases participate. Thus, cystatins may influence the intra- and extracellular catabolism of proteins and peptides (Barret, A. J. and Kirchke, H.,
Methods Enzymol
., 80:535-561 (1981)), regulate proteolytic processing of pro-hormones (Orlowski, M.,
Mol. Cell. Biochem
., 52:49-74 (1983)) and pro-enzymes (Taugner, R., et al.,
Histochemistry
, 83:103-108 (1985)), protect against penetration of normal tissues by malignant cells (Sloane, B. F.,
Semin. Cancer Biol
., 1:137-152 (1990)) or microorganisms (Bjorck, L., et al.,
Nature
, 337:385-386 (1989) and Bjorck, L., et al.,
J. Virol
., 64:941-943 (1990)) and modulate local inflammatory processes in rheumatoid arthritis (Mort, J. S., et al.,
Arthritis Rheum
., 27:509-515 (1984)) and purulent bronchiectasis (Buttle, D. J., et al.,
Scand. J. Clin. Lab. Invest
., 50:509-516 (1990)).
The cystatin superfamily has been sub-divided into families I, II and III (also called the stefin, cystatin and kininogen families, respectively), each with members differing from those of the other families in structural organization and biological distribution (Barret, A. J., et al.,
Biochem. J
., 236:312 (1986)). The family I cystatins A and B are small proteins consisting of single polypeptide chains of about 100 amino acid residues without disulfide bridges. The family II cystatins consist of polypeptide chains of approximately 120 amino acid residues with two intra-chain disulfide bonds. Finally, the family III cystatins, the kininogens, display a higher degree of structural complexity characterized by the presence of three family II cystatin-like domains, each with two disulfide bridges at positions homologous to those in family II cystatins (Muller-Esterl, W., et al.,
Transbiochem. Sci
., 11:336-339 (1986)). Family I and II cystatins are mainly present intracellularly and in secretory fluids (Abrahamson, M., et al.,
J. Biol. Chem
., 261:11282-11289 (1986)), whereas kininogens are highly concentrated in blood plasma (Adam, A., et al.,
Clin. Chem
., 31:423-426 (1985)).
At least one type II cystatin, designated cystatin C, appears to be expressed in all tissues (Abrahamson, M., et al.,
Biochem. J
., 268:287-294 (1990)). In contrast, S-type cystatins are found predominantly in saliva (Abrahamson, M., et al.,
J. Biol. Chem
., 261:11282-11289 (1986)). Cystatins and derivative peptides possess antibacterial and antiviral activities (Bjorck, et al. (1989, 1990)), consistent with their presence in secretions bathing epithelial surfaces directly exposed to the environment. The cystatins may also modulate the immune response. This could occur directly, by inhibiting cysteine proteases releases by macrophages (Bieth, J.,
Cysteine Proteinases and Their Inhibitors
, V. Turk, ed. (Walter De Gruyter & Company, New York) pp. 693-703 (1986)), or indirectly, by inhibiting the chemotaxic response and the phagocytosis-associated respiratory burst of the cells (Leung-Tack, et al.,
Biol. Chem
., 371:255-258 (1990)). This data suggests that type II cystatins might perform a variety of protective functions at epithelial surfaces. The human type II cystatin gene family consists of at least seven members.
The disease hereditary cystatin C amyloid angiopathy (HCCAA) is associated with a Glu® Leu mutation in the gene encoding cystatin C. This leads to deposition of amyloid fibrils comprised of this mutant cystatin C in the cerebral arteries, which appears to cause fatal hemorrhaging (Ghiso, J., et al.,
PNAS, USA
, 83:2974-2978 (1986)).
The effects of cystatin family protease inhibitors are varied and influence numerous functions, both normal and abnormal, in the biological processes of the mammalian system. There is a clear need, therefor, for identification and characterization of proteins that influence biological activity, both normally and in disease states. In particular, there is a need to isolate and characterize additional cystatins akin to known cystatins which may be employed, therefore, for preventing, ameliorating or correcting dysfunctions or disease or augmenting positive natural actions of such receptors.
SUMMARY OF THE INVENTION
Toward these ends, and others, it is an object of the present invention to provide polypeptides, inter alia, that have been identified as novel Cystatin F by homology between the amino acid sequence set out in
FIG. 1
(SEQ ID NO:2) and known amino acid sequences of other proteins such as human cystatin C (SEQ ID NO:3).
It is a further object of the invention, moreover, to provide polynucleotides that encode Cystatin F, particularly polynucleotides that encode the polypeptide herein designated Cystatin F.
In a particularly preferred embodiment of this aspect of the invention the polynucleotide comprises the region encoding human Cystatin F in the sequence set out in
FIG. 1
(SEQ ID NO:2).
In accordance with this aspect of the present invention there is provided an isolated nucleic acid molecule encoding a mature polypeptide expressed by the human cDNA contained in ATCC Deposit No. 97463.
In accordance with this aspect of the invention there are provided isolated nucleic acid molecules encoding human Cystatin F, including mRNAs, cDNAs, genomic DNAs and, in further embodiments of this aspect of the invention, biologically, diagnostically, clinically or therapeutically useful variants, analogs or derivatives thereof, or fragments thereof, including fragments of the variants, analogs and derivatives.
Among the particularly preferred embodiments of this aspect of the invention are naturally occurring allelic variants of human Cystatin F.
It also is an object of the invention to provide Cystatin F polypeptides, particularly human Cystatin F polypeptides, that may be employed to treat and/or prevent bacterial infection, viral infection, inflammation, protection of the eye and remodeling of the eye. Cystatin F may also be employed to regulate T-cell function and therefore regulate immune responses and may also be employed to treat immunological disorders.
In accordance with this aspect of the invention there are provided novel polypeptides of human origin referred to herein as Cystatin F as well as biologically, diagnostically or therapeutically useful fragments, variants and derivatives thereof, variants and derivatives of the fragments, and analogs of the foregoing.
Among the particularly preferred embodiments of this aspect of the invention are variants of human Cystatin F encoded by naturally occurring alleles of the human Cystatin F gene.
It is another object of the invention to provide a process for producing the aforementioned polypeptides, polypeptide fragments, variants and derivatives, fragments of the variants and deri
Gentz Reiner L.
Li Haodong
Ni Jian
Yu Guo-Liang
Ewoldt Gerald R.
Human Genome Sciences Inc.
Human Genome Sciences Inc.
Nolan Patrick J.
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