Queensland University of Technolgy

Factor Therapeutics Limited

Tissue Therapies Limited

Zee Upton

Jennifer Ann Kricker

David Leavesley

Christopher Luke Towne

Tim Dargaville

Abhishek Kashyap

Gary Keith Shooter

Brett Hollier

Adrian Charles Herington

Derek Van Lonkhuyzen

Damien Harkin

Erin A Rayment

Jesse Peet

Disclosed are methods and agents for modulating proliferation, migration and/or survival of cells. More particularly, the present invention discloses molecules that have any one or more activities selected from: inhibiting binding of vitronectin to at least one vitronectin-binding partner selected from an IGF and IGFBP, inhibiting formation of a complex comprising vitronectin and at least one vitronectin-binding partner selected from an IGF and IGFBP, or inhibiting proliferation or survival of a hyperproliferative cell (e.g., a neoplastic cell or non-neoplastic cell), or inhibiting migration or invasion of a hyperproliferative cell (e.g., a neoplastic cell or a non-neoplastic cell). Additionally, the present invention discloses the use of these molecules in methods and compositions for treating or preventing hyperproliferative cell disorders including neoplastic (e.g., cancers such as epithelial cancers) and non-neoplastic disorders.

Complex-formation-modulating agents and uses therefor

Isolated protein complexes are provided comprising keratinocyte growth factor and vitronectin, or at least domains thereof that enable binding to and activation of both a keratinocyte growth factor receptor and an integrin receptor for vitronectin. These protein complexes include synthetic proteins where the keratinocyte growth factor and vitronectin sequences are joined by a linker sequence. In particular forms, vitronectin sequences do not include a C-terminal heparin binding domain. Also provided are uses of these protein complexes for stimulating or inducing cell migration and/or proliferation in wound healing, tissue engineering, cosmetic and therapeutic treatments such as skin replacement, skin replenishment and treatment of burns where epithelial cell migration is required. In other embodiments, the invention provides inhibition of cancer cell metastasis, particularly in relation to breast cancer.

Vitronectin:keratinocyte growth factor chimeras

Isolated protein complexes are provided comprising growth factors such as IGF-I, IGF-II, EGF, bFGF, or KGF and fibronectin, or at least domains thereof that enable binding to and activation of both a growth factor receptor, and an integrin receptor-binding domain of fibronectin. These protein complexes include synthetic proteins where the growth factor and fibronectin sequences are joined by a linker sequence. Also provided are uses of these protein complexes for stimulating or inducing cell migration and/or proliferation in wound healing, tissue engineering, cosmetic and therapeutic treatments such as skin replacement, skin replenishment and treatment of burns where epithelial cell migration is required. In other embodiments, the invention provides inhibition of cancer cell metastasis, particularly in relation to breast cancer.

Fibronectin: growth factor chimeras

A method is provided for treating a disease or condition characterized by aberrant epithelial cell proliferation and/or migration. One step of the method can include administering to a mammal an agent which disrupts an isolated protein complex including: insulin-like growth factor I (IGF-I); an insulin-like growth factor binding protein (IGFBP) selected from IGFBP-3 and IGFBP-5; and vitronectin; or which prevents formation of the isolated protein complex, to thereby treat the disease or condition in the mammal. The agent is selected from the group consisting a polypeptide that is distinguished from IGF-II by substitution of at least one amino acid residue, wherein the polypeptide disrupts the isolated protein complex.

Method of treating a disease or condition characterised by aberrant epithelial cell proliferation

A cell culture medium and system are provided which eliminate or at least reduce the requirement for exogenous components such as serum and feeder cells. The cell culture medium comprises an IGF and vitronectin or fibronectin and, optionally an IGFBP, and is particularly suitable for propagating keratinocytes for subsequent use in skin growth and regeneration. This invention also relates to compositions and methods for skin growth and regeneration in situ, which utilize aerosol delivery of cultured keratinocytes.

Mammalian cell culture medium

Isolated protein complexes are provided comprising growth factors such as IGF-I, IGF-II, EGF, bFGF, KGF, VEGF or PDGF, or at least domains thereof that enable binding to and activation of both a growth factor receptor, and an integrin receptor-binding domain of vitronectin or fibronectin. These protein complexes may be in the form of oligo-protein complexes or single, synthetic proteins where the growth factor and vitronectin or fibronectin sequences are joined by a linker sequence. In particular forms, vitronectin or fibronectin sequences do not include a heparin binding domain and/or polyanionic domain. Also provided are uses of these protein complexes for stimulating or inducing cell migration and/or proliferation which may have use in wound healing, tissue engineering, cosmetic and therapeutic treatments such as skin replacement and skin replenishment and treatment of burns where epithelial cell migration is required. In other embodiments, the invention provides inhibition of cancer cell metastasis, particularly in relation to breast cancer.

Synthetic chimeric proteins comprising epidermal growth factor and vitronectin

The invention provides a dressing composition comprising a bisphosphonate matrix metalloproteinase (MMP) inhibitor covalently bound to a polymer wherein, when the dressing is contacted with a wound, substantially all of the bisphosphonate remains with the dressing composition and is unable to enter the wound tissue. The invention also provides for a method of treatment of a wound by contacting a dressing composition comprising a covalently bound MMP inhibitor with the wound fluid to thereby selectively inhibit one or more MMP's in the wound fluid without inhibiting those in the wound tissue.

Wound repair composition and method

An isolated protein complex is provided which includes a growth factor, growth factor binding protein and vitronectin. Preferably, the isolated protein complex includes an insulin-like growth factor-I, insulin-like growth factor binding protein-3 or insulin-like growth factor binding protein-5 and vitronectin. Also provided are methods of modulating cell proliferation and/or migration by administering said protein complex for the purposes of wound healing, skin repair and tissue replacement therapy. Conversely, by using agents that disrupt growth factor protein complexes formed in vivo, growth factor-driven cell proliferation and/or migration may be suppressed such as for the purposes of treating cancers, psoriasis, atherosclerosis and wounds prone to hypertrophic scarring.

Method of treating a disease or condition characterized by aberrant epithelial cell proliferation

Methods of producing growth factor complex

Isolated protein complexes are provided comprising growth factors such as IGF-I, IGF-II, VEGF or PDGF, or at least domains thereof that enable binding to and activation of both a growth factor receptor, and an integrin receptor-binding domain of vitronectin or fibronectin. These protein complexes may be in the form of oligo-protein complexes or single, synthetic proteins where the growth factor and vitronectin or fibronectin sequences are joined by a linker sequence. In particular forms, vitronectin or fibronectin sequences do not include a heparin binding domain and/or polyanionic domain. Also provided are uses of these protein complexes for stimulating or inducing cell migration and/or proliferation which may have use in wound healing, tissue engineering, cosmetic and therapeutic treatments such as skin replacement and skin replenishment and treatment of burns where epithelial cell migration is required. In other embodiments, the invention provides inhibition of cancer cell metastasis, particularly in relation to breast cancer.

Growing community of inventors

Queensland, Australia

Zee Upton