Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1997-04-03
2002-09-10
Kunz, Gary L. (Department: 1647)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S070100, C435S071100, C435S071200, C435S252300, C435S320100, C435S471000, C536S023500
Reexamination Certificate
active
06448044
ABSTRACT:
FIELD OF THE INVENTION
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 Natural Killer Cell Activating Factor II, sometimes hereinafter referred to as “NKAF II”.
BACKGROUND OF THE INVENTION
The polypeptide of the present invention is a member of the natural killer cell activating factor (NKAF) family and shows homology to NKAF and human eosinophil; major basic protein. Natural killer cells (NK cells) show a destructive effect on specific cancer cells. Lymphokines affecting the activity of these NK cells have therefore attracted attention. It is reported that interleukin-2 and interferon enhance the activity of NK cells (Herberman, R. B., et al.,
Immunol. Rev.,
44:13 (1979); Vose, B. M., et al.,
J. Immunol.
130:768 (1983) and Domzig, W. etal.,
J. Immunol.,
130:1970(1983)).
NK cells are proposed to function as natural surveillance to deter cancer development in the body (Whiteside, T. and Herberman, R. B.,
Clin. Immunol. Immunopathol
58:1-23 (1989) and Trinchieri, G.,
Adv. Immunol
47:187-376 (1989)). NK cells are also important in controlling viral infection and the regulation of hematopoiesis (Trichieri, G.,
Adv. Immunol.,
47:187-376 (1989); Kiessling, R., et al.,
Eur. J. Immunol.
7:655-663 (1977)).
The following facts indicate that NK cells play important roles in the host defense against cancer. Namely, a nude mouse lacking T cells by having a high NK activity does not always suffer from spontaneous or chemically induced carcinogenesis at a high frequency (Rygaard, J. et al.,
Immunol. Rev.,
28:43 (1975); Stutman, D., et al.,
Science,
183:534 (1974)); and the metastasis of transplanted cancer cells is promoted in a beige mouse having T cells but a genetically low NK activity (Shimamura, K. and Tamaoki, K.,
Jikken Igaku,
2:398 (1984); James E. Talmadge, et al.,
Nature,
284:622 (1980)) and a mouse having an artificially lowered NK activity (Shimamura, supra).
Human eosinophil major basic protein (MBP) has a nearly identical sequence to that of known natural killer cell activating factor I. Human MBP is one of the principal mediators of injury to parasites in tissues in allergic inflammation. MBP is stored in eosinophil crystalloid granules and released with other granule constituents during eosinophil activation. MBP has no recognized enzymatic activity but it is toxic for some helminths (Ackerman, S. J. et al.,
Am. J. Trop. Med. Hyg.,
34:735-745 (1985)) and mammalian cells (Barker, R. L. et al.,
J. Clin. Invest.
88:798-805(1991)) in vitro. MBP is expressedprincipallyin bone-marroweosinophils, but it is also synthesized in basophils and placental trophoblast x-cells (Wasmoen, T. L. et al.,
J. Exp. Med.,
170:2051-2063(1989)).
MBP stimulates the effector function of a wide variety of cells, namely MBP stimulates the noncytolytic release of histamine from human basophils and rat mass cells (O'Donnell, M. A. et al.,
J. Exp. Med.
157:1981 (1983)). MBP also stimulates neutrophils to release superoxide and ion and lysozyme, but not beta-glucuronidase or lactic dehydrogenase, and MBP enhances the expression of CR3 and P150, 95 by neutrophils. This indicates that MBP activates other cells associated with inflammation, such as basophils, platelets and neutrophils. The effector mechanisms may play a role in pathophysiology of various diseases where granule proteins are released. For example, MBP has been thought a cause for increased airway responsiveness, for example, bronchial asthma.
The effects of the natural killer cell activating factors are varied and influence numerous functions, both normal and abnormal, in the biological processes of the mammalian system. There is a clear need, therefore, for identification and characterization of proteins that influence biological activity, both normally and in diseased states. In particular, there is a need to isolate and characterize additional natural killer cell activating factors akin to known natural killer cell activating factors which may be employed, therefore, for preventing, ameliorating or correcting disfunctions 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 NKAF II by homology between the amino acid sequence set out in
FIG. 1
(SEQ ID NO:1 and 2) and known amino acid sequences of other proteins such as human eosinophil granule major basic protein.
It is a further object of the invention, moreover, to provide polynucleotides that encode NKAF II, particularly polynucleotidesthat encode the polypeptide herein designated NKAF II.
In a particularly preferred embodiment of this aspect of the invention the polynucleotide comprises the region encoding human NKAF II 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. 97465.
In accordance with this aspect of the invention there are provided isolated nucleic acid molecules encoding human NKAF II, 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 NKAF II.
It also is an object of the invention to provide NKAF II polypeptides, particularly human NKAF II polypeptides, that inhibit the growth of leukemia cells, to treat viral infection, to augment the effects of natural killer protein to treat neoplasias such as tumors and cancers, to prevent inflammation, to treat parasitic infection, to regulate hematopoiesis, to prevent damage from superoxide radicals in the body, for example, tissue injury and aging and to enhance an immunological response.
In accordance with this aspect of the invention there are provided novel polypeptides of human origin referred to herein as NKAF II 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 NKAF II encoded by naturally occurring alleles of the human NKAF II 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 derivatives, and analogs of the foregoing. In a preferred embodiment of this aspect of the invention there are provided methods for producing the aforementioned NKAF II polypeptides comprising culturing host cells having expressibly incorporated therein an exogenously-derivedhuman NKAF II-encoding polynucleotide under conditions for expression of human NKAF II in the host and then recovering the expressed polypeptide.
In accordance with another object the invention there are provided products, compositions, processes and methods that utilize the aforementioned polypeptides and polynucleotides for research, biological, clinical and therapeutic purposes, inter alia.
In accordance with certain preferred embodiments of this aspect of the invention, there are provided products, compositions and methods, inter alia, for, among other things: assessing NKAF II expression in cells
Gentz Reiner L.
Li Haodong
Ni Jian
Yu Guo-Liang
Human Genome Sciences Inc.
Human Genome Sciences Inc.
Kunz Gary L.
Landsman Robert S.
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