Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
1999-12-20
2002-09-10
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
C530S300000, C530S350000, C530S351000, C536S023500, C435S069100, C435S069500, C514S002600, C514S004300
Reexamination Certificate
active
06447766
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to methods for mobilizing hematopoietic stem cells and to a novel deamidated chemokine.
BACKGROUND OF THE INVENTION
All the members of the intercrine or chemokine family are basic heparin-binding polypeptides which have four cysteine residues which form two disulfide bridges. All these proteins which have been functionally characterized appear to be involved in proinflammatory and/or restorative functions.
In clinical situations for the use of high dose chemotherapy, the biomolecule of choice has been G-CSF. Generally, in such treatment, patients are primed with a low dose of a chemotherapeutic agent like cyclophosphamide. During the remission, the patient is treated with a CSF, such as G-CSF, which causes eventual mobilization of cells from the bone marrow to the peripheral circulation for harvesting of leukophoresed blood. The patient is thereafter administered a high dose of chemotherapy to induce clinical remission of their cancer. The resultant bone marrow failure is treated by infusion of the stored blood cells collected previously. This procedure may be modified, e.g., by the omission of the initial dose of chemotherapy and/or alternate blood collection protocols.
While the use of these hematopoietic stem cell transplantation techniques looks promising, multiple apheresis procedures are required to harvest sufficient stem cells for successful engraftment to treat severe myelosuppression when G-CSF is used alone [see, e.g., Bensinger et al,
Blood
, 81:3158 (1993) and R. Haas et al,
Sem. in Oncology
, 21:19 (1994)]. Thus, despite these significant advances and the availability of certain regulatory biomolecules, delayed recovery of hematopoiesis remains an important source of morbidity and mortality for myelosuppressed patients.
There exists a continuing need in the art for compositions and methods to enhance hematopoietic recovery, particularly in cases of chemotherapy associated myelosuppression.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides for the use of a chemokine in the preparation of a medicament for the stimulation of hematopoietic stem cells. This chemokine includes proteins derived from KC, gro&bgr;, gro&agr;, and gro&ggr;, including mature, modified, and multimeric forms of these chemokines.
In yet a further aspect, the present invention provides a method for mobilizing hematopoietic stem cells in an animal comprising administering to an animal an effective amount of a mature or modified or multimeric chemokine as described herein.
In a further aspect, the present invention provides a novel deamidated form of a modified gro&bgr; (amino acids 5-73 of SEQ ID NO: 3) which is useful for mobilizing hematopoietic stem cells.
Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1
is a graph demonstrating the effect of gro&bgr; (amino acids 1-73 of SEQ ID NO: 3) in the single agent mobilization assay of Example 1.
FIG. 2
is a graph demonstrating the effect of modified gro&bgr; (amino acids 5-73 of SEQ ID NO: 3) in the single agent mobilization assay of Example 1.
FIG. 3
is a bar graph demonstrating the comparison of phosphate buffered saline (PBS), IL-8, gro&bgr; (amino acids 1-73; SEQ ID NO: 3) and modified gro&bgr; (amino acids 5-73 of SEQ ID NO: 3) in the single agent mobilization assay.
REFERENCES:
patent: 6080398 (2000-06-01), Pelus et al.
patent: WO 91/07988 (1991-06-01), None
patent: WO 92/00327 (1992-01-01), None
patent: WO 92/01039 (1992-01-01), None
patent: WO 92/06196 (1992-04-01), None
patent: WO 94/28916 (1994-12-01), None
patent: WO 96/19234 (1996-06-01), None
Geiger T and Clarke S. J Biol Chem 262(2), Jan. 15, 1987, pp785-794. Deamidation, Isomerization, and Racemization at Asparaginyl and Aspartyl residues in peptides.*
E. Brandt, et al., “A Novel Molecular Variant of the Neutrophil-Activating Peptide NAP-2 With Enhanced Biological Activity is Truncated at the C-Terminus: Identification By Antibodies With Defined Epitope Specificity”, (1993), Molecular Immunology, vol. 30:11, pp. 979-991.
B. Moser, et al., “Interleukin-8 Antagonists Generated by N-terminal Modification”, (1993), Journal of Biological Chemistry, vol. 268:10, pp. 7125-7128.
C.A. Hérbert, et al., “Endothelial and Leukocyte Forms of IL-8”, (1990), Journal of Immunology, vol. 145:9, pp. 3033-3040.
J. Van Damme, “The neutrophil-activating proteins interleukin 8 and &bgr;-thromboglobulin: in vitro and in vivo comparison of NH2-terminally processed forms”, (1990), European Journal of Immunology, vol. 20, pp. 2113-2118.
A.M. Gronenborn, et al., “Modeling, the three-dimensional structure of the monocyte chemo-attractant and activating protein MCAF/MCP-1 on the basis of the solution structure of interleukin-8”, (1991), Protein Engineering, vol. 4:3, pp. 263-269.
J.J. Oppenheim, et al., “Properties of the Novel Proinflammatory Supergene “Intercrine” Cytokine Family”, Annual Review of Immunology, vol. 9, pp. 617-648.
S. Nourshargh, et al., “A Comparative Study of the Neutrophil Stimulatory Activity In Vitro and Pro-Inflammatory Properties In Vivo of 72 Amino Acid and 77 Amino Acid IL-8”, (1992), Journal of Immunology, vol. 148:1, pp. 106-111.
I. Clark-Lewis, et al., “Structure-Activity Relationships of Interleukin-8 Determined Using Chemically Synthesized Analogs”, (1991), Journal of Biological Chemistry, vol. 266:34, pp. 23128-23134.
Cao, et al., “gro-&bgr;, a -C-X-C- Chemokine, Is an Angiogenesis Inhibitor That Suppresses the Growth of Lewis Lung Carcinoma in Mice”, (1995), J. Exp. Med., vol. 182, pp. 2069-2077.
M.Y. Stoeckle, “Post-transcriptional regulation of gro&agr;, &bgr;, &ggr;, and IL-8 mRNAs by IL-1 &bgr;”, (1991), Nucleic Acids Research, vol. 19, No. 4, pp. 917-920.
Laterveer, et al., “Rapid Mobilization of Hematopoietic Progenitor Cells in Rhesus Monkeys by a Single Intravenous Injection of Interleukin-8”, (1996), Blood, vol. 87, No. 2, pp. 781-788.
Proost, et al., “Identification of Novel Granulocyte Chemotactic Protein (GCP-2) from Human Tumor Cells”, (1993), Journal of Immunology, vol. 150:3, pp. 1000-1010.
Cuenca, et al., “Characterization of GRO &agr;, &bgr;, and &ggr; expression in human colonic tumours: potential significance of cytokine involvement”, (1992), Surical Oncology, vol. 1, pp. 323-329.
Becker, et al., “Constitutive and stimulated MCP-1, Gro&agr;, &bgr;, and &ggr;, expression in human airway epithelium and bronchoalveolar macrophages”, (1994), American Journal of Physiology, vol. 266, pp. L278-288.
L.B. To, et al., “Single High Doses of Cyclophosphamide Enable the Collection of High Numbers of Hemopoietic Stem Cells from the Peripheral Blood”, (1990), Int'l. Society for Experimental Hematology, vol. 18, pp. 442-447.
Laterveer, et al., “Interleukin-8 Induces Rapid Mobilization of Hematopoietic Stem Cells With Radioprotective Capacity and Long-Term Myelolymphoid Repopulating Ability”, (1995), Blood, vol. 85, pp. 2269-2275.
King Andrew Garrison
Pelus Louis Martin
Qian Yanqiu
Hall Linda E.
King William T.
Mertz Prema
Prasad Sarada C
SmithKline Beecham Corporation
LandOfFree
Method of mobilizing hematopoietic stem cells does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method of mobilizing hematopoietic stem cells, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of mobilizing hematopoietic stem cells will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2901071