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Researchers Submit Patent Application, "Fibronectin: Growth Factor Chimeras", for Approval

The patent's assignee for patent serial number 511776 is Queensland University of Technology.

News editors obtained the following quote from the background information supplied by the inventors: "A number of peptide growth factors involved in a broad range of cellular processes including hyperplasia, DNA synthesis, differentiation, cell cycle progression, and inhibition of apoptosis are known, and include the insulin-like growth factors (IGFs, e.g., IGF-I and IGF-II) (Jones & Clemmons, 1995, Endocrine Rev. 16 3; Wood & Yee, 2000, J. Mammary Gland Biology and Neoplasia 5 1), EGF (Heldin et al., 1981, Science 4 1122), bFGF (Taraboletti et al., 1997, Cell Growth. Differ. 8 471), and KGF (Marchese et al., 1990, J. Cell Physiol. 144 326). These effects are mediated through binding to their cognate tyrosine-kinase linked cell surface receptors, the type 1 IGF receptor (IGF-IR), EGF receptor, bFGF receptor, and KGF receptor, respectively. The IGFs are also tightly regulated by a family of specific binding proteins, termed IGFBPs, whose primary role is to bind free IGFs and thereby moderate their half-life, specificity and activity (Clemmons, 1998, Mol. Cell. Endoerinol. 140 19).

"Fibronectin is a high molecular mass adhesive glycoprotein found in all vertebrates. Fibronectin plays a role in cell adhesion, cell morphology and surface architecture. It's main function seems to be its involvement in cellular migration during development, tissue repair and wound healing, regulation of cell growth, and differentiation (Alitalo & Vaheri, 1982, Adv. Cancer Res. 37 111; Yamada, 1983, Annu. Rev. Biochem. 62 761; Hynes, 1985, Annu. Rev. Cell Biol. 1 67). Fibronectin polymorphism is due to alternative splicing patterns in three regions (ED-A, ED-B and IIICS) of the single fibronectin primary transcript (Petersen et al., 1983, Proc. Natl. Acad. Sci. USA 80 137; Schwarzbauer et al., 1983, Cell 35 421; Kornblihtt et al., 1984, Nucleic Acids Res. 12 5853). The exact composition of fibronectin depends on the tissue type and/or cellular conditions. In humans, there are potentially 20 different forms of fibronectin, most arising from alternative splicing of some type 3 modules (Potts and Campbell, 1994, Curr. Opin. Cell Biol. 6 648). Expression of fibronectin splicing variants appears to be both developmentally regulated and tissue-specific.

"Fibronectin has the ability to bind a number of extracellular molecules, including heparin, collagen and hyaluronic acid. Fibronectin organizes cell-cell interactions and cellular interaction with the extracellular matrix by binding to different components of the extracellular matrix and to membrane-bound fibronectin receptors (integrins) on cell surfaces.

"However, the relative contributions of growth factors and fibronectin, and their respective domains, present in protein complexes, in terms of stimulating biological responses such as cell migration and/or proliferation, have remained elusive."

As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventors' summary information for this patent: "The present inventors have discovered that protein complexes in the form of synthetic chimeras comprising growth factors such as IGF-I, IGF-II, EGF, bFGF, or KGF and FN stimulate cell migration and/or proliferation by binding and synergistically co-activating cognate growth factor receptors and FN-binding integrin receptors.

"Therefore, the invention is broadly directed to isolated protein complexes that comprise a receptor-binding domain of a growth factor domain and at least a domain of fibronectin that is capable of binding an integrin receptor, wherein the isolated protein complex can co-activate the growth factor and integrin receptor to thereby elicit a biological response.

"In a first aspect, the invention provides an isolated protein complex in the form of a synthetic chimeric protein comprising an amino acid sequence of:

"(i) a growth factor, or at least a domain of a growth factor which is capable of binding a cognate growth factor receptor; and

"(ii) fibronectin, or a fragment of fibronectin comprising at least an integrin-binding domain of fibronectin.

"Preferably, according to the aforementioned aspects the growth factor is TGF-I, IGF-II, EGF, bFGF, or KGF.

"Preferably, the integrin receptor is an .alpha..sub.1 or an .alpha..sub.4 integrin.

"This aspect of the invention also contemplates an amino acid sequence of one or more additional fragments of fibronectin in the synthetic chimeric protein.

"This aspect of the invention also includes within its scope amino acid deletions, additions, substitutions and/or mutations of amino acid sequences corresponding to (i) and (ii) above, as well as amino acid sequences corresponding to the one or more additional fragments of fibronectin.

"In a second aspect, the invention provides an isolated nucleic acid encoding the isolated protein complex of the first aspect.

"In a third aspect, the invention provides a genetic construct comprising the isolated nucleic acid of the second aspect operably linked to one or more regulatory sequences in an expression vector.

"Preferably, the genetic construct is an expression construct.

"In a fourth aspect, the invention provides a host cell comprising the genetic construct of the third aspect.

"In a fifth aspect, the invention provides a pharmaceutical composition comprising the isolated protein complex of the first aspect and a pharmaceutically-acceptable carrier, diluent or excipient.

"This aspect of the invention also contemplates a pharmaceutical composition comprising the host cell of the fourth aspect, which cell expresses said synthetic protein(s).

"In a sixth aspect, the invention provides an antibody specific for the synthetic protein of the first aspect.

"In a seventh aspect, the invention provides a method of promoting cell migration including the step of using a synthetic protein to bind both a growth factor receptor and an integrin receptor.

"Preferably, the growth factor receptor is IGF-IR, EGF receptor, bFGF receptor, or KGF receptor.

"Preferably, the integrin receptor is an .alpha..sub.1 or an .alpha..sub.4 integrin.

"In a preferred embodiment, this aspect of the invention relates to promotion or induction of epithelial/keratinocyte/fibroblast cell migration and/or proliferation to facilitate wound healing in mammals, preferably humans.

"Preferably, said synthetic protein is as according to the first aspect of the invention.

"In an eighth aspect, the invention provides a method of preventing cell migration and/or proliferation, including the step of preventing, inhibiting or otherwise reducing binding of both a growth factor receptor and an integrin receptor by a complex comprising a growth factor and fibronectin.

"Preferably, the growth factor receptor is IGF-IR, EGF receptor, bFGF receptor, or KGF receptor.

"Preferably, the integrin receptor is an .alpha..sub.1 or an .alpha..sub.4 integrin.

"In a preferred embodiment, this aspect of the invention relates to prevention or inhibition of metastatic cancer cell migration and/or proliferation in mammals, preferably humans.

"A particular example contemplated by this aspect of the invention is prevention or inhibition of breast cancer metastasis.

"It will also be appreciated that the methods of the seventh and eighth aspects may encompass prophylactic and therapeutic methods of treatment.

"In a ninth aspect, the invention provides use of the isolated protein complex of the first aspect to produce a molecule that:

"(i) is an agonist of protein complexes comprising a growth factor and fibronectin; or

"(ii) is an antagonist of protein complexes comprising a growth factor and

"fibronectin.

"In one embodiment, the invention provides use of the synthetic protein of the first aspect to produce a molecule that: (i) is an agonist of GF-I:FN, IGF-II:FN, EGF:FN, bFGF:FN, KGF:FN, or IGF-I:IGFBP:FN protein complexes; or (ii) is an antagonist of IGF-I:FN, IGF-II:FN, EGF:FN, bFGF:FN, KGF:FN, or IGF-I:IGFBP:FN protein complexes.

"Agonists and/or antagonists produced according to this aspect of the invention may have particular efficacy in promoting wound healing, tissue engineering, skin regeneration and/or prevention of cancer cell metastasis or hyperproliferative disorders of the skin, such as scarring and psoriasis.

"In a tenth aspect, the invention provides a biomaterial that comprises the isolated protein complex of the first aspect.

"In particular embodiments the biomaterial may be a surgical implant, prosthesis, scaffold, wound or burn dressing, or the like suitably impregnated, coated or otherwise comprising an isolated protein complex of the invention."

For additional information on this patent application, see: Upton, Zee; Van Lonkhuyzen, Derek. Fibronectin: Growth Factor Chimeras. U.S. Patent Serial Number 511776, filed November 30, 2010, and posted January 10, 2013. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser'Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=3392&p=68&f=G&l=50&d=PG01&S1=20130103.PD.&OS=PD/20130103&RS=PD/20130103

Keywords for this news article include: Biotechnology, Cancer, Oncology, Integrins, rev Genes, Proteomics, Amino Acids, Viral Genes, Fibronectins, Medical Devices, Serum Globulins, Chimeric Protein, Genetic Phenomena, Genome Components, Membrane Proteins, Peptide Receptors, Genetic Structures, Immunologic Receptors, Membrane Glycoproteins, Growth Factor Receptors.

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