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US 7,396,810 B1Granted
Compositions and methods for treating cancer by modulating HER-2 and EGF receptors
AssigneeOregon Health Sciences University
InventorGail M. Clinton
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AssigneeOregon Health Sciences University
InventorGail M. Clinton
Estimating the term…
An alternative HER-2/neu product, herstatin, consists of subdomains I and II from the ectodomain of p185HER-2 and a unique 79 amino acid C-terminus encoded by intron 8. Recombinant herstatin added to cells was found to bind to and inhibit p185HER-2. The effects of ectopic expression of herstatin in combination with either p185HER-2 or with its homolog, the EGF receptor, in several cell lines was studied. Cotransfection of herstatin with HER-2 inhibited p185HER-2 levels and caused an approximate 8 fold reduction in p185 tyrosine phosphorylation. Inhibition of p185HER-2 tyrosine phosphorylation corresponded to a dramatic decline in colony formation by cells that coexpressed p185HER-2 and herstatin. Herstatin also interfered with EGF activation of the EGF receptor in cotransfected cells demonstrated by impaired receptor tyrosine phosphorylation, reduced receptor down-regulation, and growth suppression. For both p185HER-2 and the EGF receptor, the extent of inhibition was affected by the expression levels of herstatin relative to the receptor. Herstatin is an autoinhibitor of p185HER-2 and expands its inhibitory activity to another member of the group I family of receptor tyrosine kinases, the EGF receptor.
A method for treating a solid tumor characterized by expression of EGF receptor, comprising administering, to a subject in need thereof determined to have a tumor expressing the EGF receptor, an agent that binds to the extracellular domain of EGF receptor, wherein the agent is selected from the group consisting of (a) an isolated polypeptide comprising the amino acid sequence of SEQ ID NOS:11, 15 or 17-26, or fragments thereof of about 50 to 79 contiguous residues in length, wherein the polypeptide binds to the extracellular domain of EGF receptor with an affinity binding constant of at least 108 M−1, (b) an isolated and glycosylated polypeptide comprising the amino acid sequence of SEQ ID NOS:12, 38 or 27-36, or fragments thereof of about 80 to 419 contiguous residues in length, wherein the C-terminal 79 contiguous amino acids are present, wherein at least one N-linked glycosylation site is present, and wherein the polypeptide binds to the extracellular domain of EGF receptor with an affinity binding constant of at least 108 M−1, (c) a monoclonal antibody that binds to the extracellular domain of EGF receptor, and (d) combinations thereof, with the proviso that where the composition comprises the monoclonal antibody it also comprises at least one of the agents of (a) or (b).
A method for treating a solid tumor characterized by expression of EGF receptor, comprising administering, to a subject in need thereof, an agent that binds to the extracellular domain of EGF receptor;
A method for treating a solid tumor characterized by expression of EGF receptor, comprising administering, to a subject in need thereof, an agent that binds to the extracellular domain of EGF receptor, wherein the agent comprises the amino acid sequence of SEQ ID NO:12.
A method for treating a solid tumor characterized by expression of EGF receptor, comprising administering, to a subject in need thereof determined to have a tumor expressing the EGF receptor, an agent that binds to the extracellular domain of EGF receptor, wherein the agent is selected from the group consisting of (a) an isolated polypeptide comprising the amino acid sequence of SEQ ID NO:1, or fragments thereof of about 50 to 79 contiguous residues in length, wherein the polypeptide binds to the extracellular domain of EGF receptor with an affinity binding constant of at least 108 M−1, (b) an isolated and glycosylated polypeptide comprising the amino acid sequence of SEQ ID NO:2, or fragments thereof of about 80 to 419 contiguous residues in length, wherein the C-terminal 79 contiguous amino acids are present, wherein at least one N-linked glycosylation site is present, and wherein the polypeptide binds to the extracellular domain of EGF receptor with an affinity binding constant of at least 108 M−1, (c) a monoclonal antibody that binds to the extracellular domain of EGF receptor, and (d) combinations thereof, with the proviso that where the composition comprises the monoclonal antibody it also comprises at least one of the agents of (a) or (b).
Dependencies are inferred from the claim text.