Fibroblast growth factor receptor-immunoglobulin fusion

Details Fibroblast growth factor receptor-immunoglobulin fusion Fibroblast growth factor receptor-immunoglobulin fusion

2000-02-07

2003-12-02

Kemmerer, Elizabeth (Department: 1646)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

C435S320100, C536S023400, C530S350000, C530S387100, C514S002600

Reexamination Certificate

active

06656728

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to compositions and methods for inhibiting cell proliferation, especially angiogenesis. The invention specifically relates to fusions of the extracellular domain of a fibroblast growth factor receptor (FGFR) with an immunoglobulin (Ig), especially an Ig Fc region, as an FGFR antagonist. The invention also relates to novel FGFR-Ig fusion proteins.
BACKGROUND OF THE INVENTION
Angiogenesis, or development of new blood vessels, is implicated in a host of diseases including tumorigenesis, metastasis and tumor growth, retinopathies, neovascular ocular disorders, and postangioplasty or postatherectomy restenosis (Bicknell et al. (1996)
Curr. Opin. Oncol
. 8: 60-65; Gariano et al. (1996)
Survey Ophthalmol
. 40: 481-490; and Wilcox, J. N. (1993)
Am. J. Cardiol
. 72: 88E-95E).
Expression and secretion of angiogenic factors by tumors has been investigated. It has been suggested that because tumors express multiple angiogenic factors, broad spectrum antagonists of angiogenesis can provide effective means of tumor stabilization. Anti-angiogenic approaches to tumor therapy have been defined to involve interference with growth, migration and differentiation of blood vessels associated with tumor growth. Anti-angiogenic agents have been categorized to include protease inhibitors, modulators of cytokines, heparin-like molecules, and antagonists of vascular growth factors. Growth factor antagonists have been categorized to include heparin-like molecules, angiogenin antagonists, antisense fibroblast growth factor, DS 4152, suramin analogs, and protein-bound saccharide-K (Bicknell et al. (1996)
Curr. Opin. Oncol
. 8: 60-65).
Various growth factors and growth factor receptors are known to be associated with particular types of tumors. At the molecular level, growth factors and growth factor receptors belong to multi-member families categorized based on structural and functional characteristics. Fibroblast growth factor (FGF) is involved in growth and differentiation of a number of cell types, and can contribute significantly to tumorigenicity. The FGF family includes FGF-1 or acidic FGF (aFGF), FGF-2 or basic FGF (bFGF), FGF-7 or KGF, oncogene products FGF-3 or int-2, hsp/Kaposi-FGF (K-FGF or FGF-4), FGF-5, and FGF-6. These members of the FGF family bind heparin, may exhibit mitogenic activity toward various cells, and may be potent mediators of angiogenesis. (Pontaliano et al. (1994)
Biochemistry
33: 10229-10248; Kiefer et al. (1991)
Growth Factors
5: 115-127).
FGF receptor (FGFR) includes FGFR1 or flg, FGFR2 or bek, FGFR3 or cek2, and FGFR4 (Kiefer et al. (1991)
Growth Factors
5: 115-127). FGFR belongs to the tyrosine kinase family of receptors and to the immunoglobulin (Ig) supergene family. mRNA splicing variants of FGFR exist that produce secreted and transmembrane forms of the receptors with various ligand binding affinities and specificities. In transmembrane forms of the receptor, the tyrosine kinase domain is intracellular and the (Ig)-like domains are extracellular. Both transmembrane and secreted forms bind FGF. Heparin and related compounds promote the interaction between FGF and FGFR by acting as cofactors in dimerization or higher oligomerization of FGFR. The dimerization process is thought to be necessary for activation of FGFR.
FGFR fusion proteins present the possibility of constructing preoligomerized, particularly predimerized forms of FGFR. Such preoligomerized forms would be useful as potent and therapeutically effective inhibitors of FGF-mediated cell proliferation. FGFR antagonists would be especially useful to treat diseases involving angiogenesis.
Monomeric forms of the FGFR extracellular domain have been used to inhibit FGF-mediated events (Kiefer et al. (1991)
Growth Factors
5:115-127). However, preoligomerized forms of the FGFR extracellular domain have not been used as FGFR antagonists. Thus, there is a need for providing preoligomerized forms of FGFR extracellular domain as antagonists of FGFR. Given the implicated role of this ligand/receptor system in angiogenesis, and the breadth of involvement of angiogenesis in several malignancies and other disorders, the approach promises a useful tool in providing an effective therapy for such disorders.
Receptor-immunoglobulin (Ig) fusion proteins have been used in the art. For example, an Ig fusion protein with a human tumor necrosis factor receptor has been applied to treatment of rheumatoid arthritis and septic shock (Moreland et al. (1997)
New Engl. J Med
. 337: 141-147; Fisher et al. (1996)
New Engl. J Med
. 334: 1697-1702). An Ig fusion protein with urokinase plasminogen activator (uPA) has been used as a uPA receptor antagonist to inhibit angiogenesis and tumor growth (Min et al. (1996)
Cancer Res
. 56: 2428-2433). WO 95/21258 describes using FGFR-Ig fusion proteins in a method of identifying agonists and antagonists of FGFR. However, construction and use of the specific FGFR-Ig fusion proteins as antagonists of FGFR has not been suggested. Other examples of receptor-Ig fusion proteins include those described in U.S. Pat. Nos. 5,726,044; 5,707,632; and 5,750,375.
SUMMARY OF THE INVENTION
The invention is directed at providing oligomerized forms of FGFR as FGFR antagonists, constructed by fusing extracellular domains of FGFR with heterologous oligomerization domains. Compositions comprising polypeptides and polynucleotides encoding the fusion polypeptides are provided, as well as methods of using the compositions for treating disorders mediated by FGF, FGFR or angiogenesis, such as cancer and other hyperproliferative diseases.


REFERENCES:
patent: 5116964 (1992-05-01), Capon et al.
patent: 5155027 (1992-10-01), Sledziewski et al.
patent: 5229501 (1993-07-01), Keifer et al.
patent: 5567584 (1996-10-01), Sledziewski et al.
patent: 5707632 (1998-01-01), Williams et al.
patent: 5716805 (1998-02-01), Srinivasan et al.
patent: 5726044 (1998-03-01), Lo et al.
patent: 5750375 (1998-05-01), Sledziewski et al.
patent: 6255454 (2001-07-01), Keifer et al.
patent: 0 325 224 (1989-01-01), None
patent: 0 314 317 (1989-05-01), None
patent: 0 545 343 (1993-06-01), None
patent: 0 721 983 (1996-07-01), None
patent: 0 801 307 (1997-03-01), None
patent: 0 464 533 (1998-07-01), None
patent: WO 89/02922 (1989-04-01), None
patent: WO 91/00916 (1991-01-01), None
patent: WO 91/08298 (1991-06-01), None
patent: WO 91/11459 (1991-08-01), None
patent: WO 94/04690 (1994-03-01), None
patent: WO 95/21258 (1995-08-01), None
patent: WO 97/28272 (1997-08-01), None
Ashkenazi, Avi, et al., Protection Against Endotoxic Shock by a Tumor Necrosis Factor Receptor Immunoadhesin, Medical Sciences (1991) 10535-10539, vol. 88.
Bicknell, Roy, et al., Mechanisms and Therapeutic Implications of Angiogenesis, Current Opinion in Oncology (1996) 60-65, vol. 8.
Duncan, Alexander, et al., The binding site for Clq on IgG, Nature (1988) 738-740, vol. 332, No. 21.
Fisher, Charles J., et al., Treatment of Septic Shock with the Tumor Necrosis Factor Receptor:Fc Fusion Protein, The New England Journal of Medicine (1996) 1697-1702, vol. 334, No. 26.
Kiefer, Michael, C., et al., Molecular Cloning of a Human Basic Fibroblast Growth Factor Receptor cDNA and Expression of a Biologically Active Extracellular Domain in a Baculovirus System, Growth Factors (1991) 115-127, vol. 5.
Kim, K. Jin, et al., Inhibition of Vascular Endothelial Growth Factor-Induced Angiogenesis Suppresses Tumour Growth in vivo, Nature (1993) 841-844, vol. 362.
Lenschow, Deborah, et al., Long-Term Survival of Xenogeneic Pancreatic Islet Grafts Induced by CTLA4lg. Science (1992) 789-792, Vol 257.
Linsley, Peter, et al., Immunosuppression in vivo by a Soluble Form of the CTLA-4 T Cell Activation Molecule, Science (1992) 792-794, vol. 257.
Millauer, Birgit, et al., Glioblastoma Growth Inhibited in vivo by a Dominant-Negative Flk-1 Mutant, Nature (1994) 576-579, vol. 367.
Min, Hye Yeong, et al., Urokinase Receptor Antagonists Inhibit Angiogenesis and Primary Tumor Growth in Syngenic Mice, Cancer Research (1996) 2428-2433, vol. 56.
Mohler, Kendall, et al.,

Affiliated with

Also associated with

Rating

Fibroblast growth factor receptor-immunoglobulin fusion does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Fibroblast growth factor receptor-immunoglobulin fusion, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Fibroblast growth factor receptor-immunoglobulin fusion will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3105455