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Methods of using flt3-ligand in the treatment of cancer

a cancer and ligand technology, applied in the field of mammalian flt3ligands, can solve the problems of limiting the use of cytoreductive therapies, increasing morbidity, mortality, and increasing the risk of infection and bleeding disorders, so as to improve the quality of life of patients, promote hair growth, and raise the immune response of patients

Inactive Publication Date: 2007-09-06
CELLDEX THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a new protein called flt3-ligand (flt3-L) and its use in various applications. The invention includes methods for producing flt3-L and using it to expand progenitor or stem cells for use in gene therapy and treatment of various conditions such as myelodysplastic syndrome, aplastic anemia, HIV infection, and infertility. The invention also includes the use of flt3-L in pharmaceutical compositions and in the stimulation of non-hematopoietic stem cells. The technical effects of the invention include the improved ability to expand stem cells and the use of flt3-L in gene therapy and treatment of various conditions.

Problems solved by technology

Side effects typically result from cytotoxic effects upon normal cells and can limit the use of cytoreductive therapies.
As a result of myelosuppression, patients develop cytopenia, or blood cell deficits, that increase risk of infection and bleeding disorders.
Cytopenias increase morbidity, mortality, and lead to under-dosing in cancer treatment.
This can result in extended disease-free remission for some even poor-prognosis patients.
Nevertheless, high-dose chemotherapy is toxic and many resulting clinical complications are related to infections, bleeding disorders and other effects associated with prolonged periods of myelosuppression.
Treatment of theses syndromes with retinoids, vitamin D, and cytarabine has not been successful.
Most of the patients suffering from these syndromes are elderly and are not suitable candidates for bone marrow transplantation or aggressive antileukemic chemotherapy.
Similarly to myelodysplastic syndrome, most patients suffering from this syndrome are elderly and are unsuitable for bone marrow transplantation or for aggressive antileukemic chemotherapy.
Recombinant EPO has been shown to normalize the patient's hematocrit and hemaoglobin levels, however, usually very high doses are required.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Flt3-Receptor:Fc Fusion Protein

[0092] This example describes the cloning of murine flt3 cDNA, and the construction of an expression vector encoding a soluble murine flt3-receptor:Fc fusion protein for use in detecting cDNA clones encoding flt3-L. Polymerase chain reaction (PCR) cloning of the flt3 cDNA from a murine T-cell was accomplished using the oligonucleotide primers and the methods as described by Lyman et al., Oncogene, 8:815-822, (1993), incorporated herein by reference. The cDNA sequence and encoded amino acid sequence for mouse flt3 receptor is presented by Rosnet et el., Oncogene, 6:1641-1650, (1991), hereby incorporated by reference. The mouse flt3 protein has a 542 amino acid extracellular domain, a 21 amino acid transmembrane domain, and a 437 amino acid cytoplasmic domain.

[0093] Prior to fusing the murine flt3 cDNA to the N-terminus of cDNA encoding the Fc portion of a human IgG1 molecule, the amplified mouse flt3 cDNA fragment was inserted into Asp7...

example 2

Screening Cells for Flt3:Fc Binding

[0098] Approximately 100 different primary cells and cell lines falling into the following general categories: primary murine fetal brain cells, murine fetal liver cell lines, rat fetal brain cell lines, human lung carcinoma (fibroblastoid) cell lines, human and murine lymphoid and myeloid cell lines were assayed for flt3:Fc binding. Cell lines were incubated with flt3:Fc, followed by a biotinylated anti-human Fc antibody, followed by streptavidin-phycoerythrin (Becton Dickinson). The biotinylated antibody was purchased from Jackson Immunoresearch Laboratories. Streptavidin binds to the biotin molecule attached to the anti-human Fc antibody, which in turn binds to the Fc portion of the flt3:Fc fusion protein. Phycoerythrin is a fluorescent phycobiliprotein which serves as a detectable label. The level of fluorescence signal was measured for each cell type using a FACScan® flow cytometer (Becton Dickinson). The cell types deemed positive for flt3:F...

example 3

Isolation and Cloning of Flt3 L cDNA From Murine T-Cell cDNA Library

[0099] A murine T-cell cDNA library of cell line P7B-0.3A4 was chosen as a possible source of flt3-L cDNA. P7B-0.3A4 is a murine T cell clone that is Thy1.2+, CD4−, CD8−, TCRab±, CD44+. It was originally cloned at a cell density of 0.33 cells / well in the presence of rHuIL-7 and immobilized anti-CD3 MAb, and was grown in continuous culture for more than 1 year by passage once a week in medium containing 15 ng / ml rHuIL-7. The parent cell line was derived from lymph node cells of SJL / J mice immunized with 50 nmoles PLP139-151 peptide and 100 μg Mycobacterium tuberculosis H37Ra in Incomplete Freund's Adjuvant. PLP is the proteolipid protein component of the myelin sheath of the central nervous system. The peptide composed of amino acids 139-151 has previously been shown to be the encephalogenic peptide in experimental autoimmune encephalomyelitis (EAE), a murine model for multiple sclerosis in SJL / J mice. (Touhy, V. K....

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Abstract

Ligands for flt3 receptors capable of transducing self-renewal signals to regulate the growth, proliferation or differentiation of progenitor cells and stem cells are disclosed. The invention is directed to Flt3-ligand as an isolated protein, the DNA encoding the Flt3-ligand, host cells transfected with cDNAs encoding Flt3-ligand, compositions comprising Flt3-ligand and methods of using Flt3-ligand in hematopoietic cell transplantation.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. application Ser. No. 08 / 994,468, filed May 26, 2000, which was a continued prosecution application of U.S. application Ser. No. 08 / 994,468, filed Dec. 19, 1997, which is a continuation of U.S. application Ser. No. 08 / 444,627, filed May 19, 1995, now abandoned, which is a divisional of U.S. application Ser. No. 08 / 243,545 filed May 11, 1994, now allowed and issued as U.S. Pat. No. 5,554,512, which is a continuation-in-part of U.S. application Ser. No. 08 / 209,502 filed Mar. 7, 1994, now abandoned,FIELD OF THE INVENTION [0002] The present invention relates to mammalian flt3-ligands, the nucleic acids encoding such ligands, processes for production of recombinant flt3-ligands, pharmaceutical compositions containing such ligands, and their use in various therapies. BACKGROUND OF THE INVENTION [0003] Blood cells originate from hematopoietic stem cells that become committed to differentiate along certai...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00A01K67/027A61K35/28A61K38/00A61K38/18A61K38/19A61K48/00C07K14/475C12N5/0789C12N15/85
CPCA01K67/0275A01K2217/05A61K35/28A61K45/06A61K38/193A61K38/1816C12N2510/00A01K2227/105A01K2267/025A01K2267/03A01K2267/0331A01K2267/0381A61K38/00A61K48/00C07K14/475C07K2319/00C07K2319/30C12N5/0647C12N15/8509C12N2501/22C12N2501/23C12N2501/26A61K2300/00A61P35/00
Inventor LYMAN, STEWART D.BECKMANN, M. PATRICIA
Owner CELLDEX THERAPEUTICS INC
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