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  Binding peptides specific for the extracellular domain of erbb2 and uses thereforUSPTO Application #: 20060276379Title: Binding peptides specific for the extracellular domain of erbb2 and uses therefor Abstract: The invention provides methods and compositions for diagnosing and treating subjects using EBPs. Specifically disclosed are peptides and peptidomimetics that bind selectively to the extracellular domain of ErbB2. These compositions are useful in the prevention and treatment of disorders characterized by ErbB2 overexpression (e.g., breast cancer). (end of abstract)
Agent: Wolf Greenfield & Sacks, PC - Boston, MA, US Inventors: David N. Krag, Stephanie C. Pero, Lyn Oligino Related Keywords: bind, breast, breast cancer, cancer, domain, prevention USPTO Applicaton #: 20060276379 - Class: 514009000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides The Patent Description & Claims data below is from USPTO Patent Application 20060276379. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application is a continuation of application Ser. No. 10/272,437, filed on Oct. 15, 2002, now allowed, which claims priority under 35 U.S.C. .sctn.119 to U.S. provisional application Ser. No. 60/329,183 filed Oct. 12, 2001, the entire contents of each is incorporated by reference herein. FIELD OF THE INVENTION [0003] The invention relates to peptides and peptidomimetics that bind to the extracellular domain of ErbB2, and their use in diagnosis, prevention and treatment of disorders associated with overexpression of ErbB2 (e.g., breast cancer). BACKGROUND OF THE INVENTION [0004] One major drawback of most cancer therapeutics is the lack of specificity and associated toxicity to normal tissues. A significant advance in therapeutic effectiveness would be likely achieved if cytotoxic agents could be delivered specifically to tumor cells, with minimal delivery to normal tissue. Conjugation of cytotoxic agents to molecules that bind specifically to a tumor target found would then enable tumor-specific delivery and would reduce non-specific toxicity. [0005] Molecules that are found specifically on the surface of cancer cells are especially promising targets for tumor-specific homing molecules. An example of such a cell surface molecule is ErbB2 (also known as HER2 or neu). ErbB2 is a member of the ErbB family of growth factor receptors, which includes ErbB1 (also known as epidermal growth factor receptor). ErbB2 is a membrane protein containing a cysteine-rich extracellular domain (ECD), a transmembrane domain, and an intracellular tyrosine kinase domain. It is overexpressed on the surface of breast cancer cells in approximately 30% of newly diagnosed patients and is associated with a poor prognosis. Importantly, metastatic tumor cells in the bone marrow of 60-70% of breast cancer patients overexpress ErbB2 on their surface (Pantel et al., J Natl Cancer Inst 85:1419; Braun et al., Cancer Research, 61:1890). Therefore, ErbB2 is an extremely promising target molecule for some forms of cancer. SUMMARY OF THE INVENTION [0006] The invention relates to the identification of peptides that specifically bind to the extracellular domain of ErbB2. ErbB2 overexpression is a hallmark of many forms of cancer, including most notably breast cancer, ovarian cancer, stomach cancer, lung cancer and bladder cancer, among others. Accordingly, the discovery of small, preferably peptide, molecules that bind to ErbB2 facilitates detection, prevention and treatment of disorders characterized by overexpression of ErbB2 (including those that overexpress ErbB2), such as those listed above. Prior to the invention, an antibody to ErbB2 (i.e., Herceptin) had been identified, and tested clinically. The small peptides of the present invention have pharmacokinetic properties superior to larger molecules such as antibodies. [0007] Accordingly, in one aspect, the invention provides ErbB2 binding peptides, referred to herein as EBP. The invention provides at least 20 EBP, the sequences of which are provided below. Some of the EBP of the invention share common sequence elements. In preferred embodiments, the EBP of the invention bind to the extracellular domain of ErbB2. The EBP include both the peptides described herein as well as their functional equivalents. In preferred embodiments, the functional equivalents are peptides that have at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% identity with the peptides described herein. The functional equivalents may be different from the peptides described herein at one, two, three, four, or more amino acid positions. In the most common instances, such differences will involve conservative amino acid substitutions. [0008] Thus, in one aspect, the invention provides a composition comprising a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38 and SEQ ID NO:39, and functional equivalents thereof, including functionally equivalent fragments thereof. These peptides are referred to herein as ErbB2-binding peptides (i.e., EBP), and each is designated with a unique number (e.g., EBP-1, EBP-2, EBP-3, EBP-4, EBP-5, EBP-6, EBP-7, EBP-8, EBP-9, EBP-10, EBP-11, EBP-12, EBP-13, etc.). As indicated in the Brief Description of the Sequence Listing, SEQ ID NO:1 through to SEQ ID NO:13 and SEQ ID NO:33 through to SEQ ID NO:39 represent the amino acid sequences of EBP-1 through to EBP-13 and EBP-14 through to EBP-20, respectively. [0009] In one embodiment, the EBP is cyclic or is capable of being cyclized via, for example, a disulfide bond, a thio-ether linkage or a peptide bond. In another embodiment, the peptide is conjugated to an agent. The agent may be selected from the group consisting of a toxin, a radioactive molecule, a detectable label, an imaging agent, a diagnostic agent, a chemotherapeutic agent, an anti-angiogenic agent, an anti-cancer agent, an immunomodulatory agent, an antigen or antigenic moiety, an apoptosis agent, and a translocating agent. The translocating agent can be used to translocate the peptide or preferably a therapeutic agent attached to the peptide into the cell in order to deliver the therapeutic agent to the cell. In another embodiment, the peptide is used together with an agent that functions in the cytoplasmic compartment of a cell, such as for example an agent that inhibits the cytoskeleton, or inhibits spindle formation. Several of these latter types of agents are known to be chemotherapeutic agents. In yet another embodiment, the peptide is conjugated to another peptide such as one with binding specificity for EGFR, ErbB3, or ErbB4. In another embodiment, the composition comprises the peptide with a liposome or viral particle (e.g., for delivery in gene therapy). [0010] The functional equivalents of EBP can be comprised of amino acids or peptidomimetics. In one embodiment, the functional equivalent is selected from the group consisting of a phage library member, a synthetic peptide library member, a combinatorial chemical library member, and a peptidomimetic. [0011] The foregoing embodiments relating to the peptides and functional equivalents of the invention apply equally to all aspects of the invention. [0012] In one embodiment, the composition further comprises a pharmaceutically acceptable carrier, and optionally, the peptide or functional equivalent thereof is present in an effective amount. In other embodiments, the composition further comprises another therapeutic agent including but not limited to an anti-cancer agent. The composition may be provided in a sustained release vehicle. In various embodiments of the invention, the ErB2 binding peptides bind the extracellular domain of ErbB2 and, importantly, also inhibit the phosphorylation of ErbB2 (e.g., at particular tyrosine or serine residues, as described herein). [0013] The invention also provides for isolated nucleic acid molecules that code for ErbB2 binding peptides. Thus, in yet another aspect, an isolated nucleic acid molecule is provided comprising (a) a nucleic acid molecule which codes for a peptide comprising an amino acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38 and SEQ ID NO:39 (i.e., SEQ ID NO:1 through to SEQ ID NO:13 inclusive and SEQ ID NO:33 through to SEQ ID NO:39 inclusive) or functionally equivalent fragments thereof; (b) degenerates of (a); and (c) complements of (a) and (b). [0014] In some embodiments, the isolated nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of SEQ ID NO:14 through to SEQ ID NO:26 and SEQ ID NO:40 through to SEQ ID NO:46, inclusive, and degenerates thereof. Using the nucleic acid codons provided herein, one of ordinary skill in the art will readily determine the nucleic acid sequences that are degenerates thereof. The invention similarly embraces these latter nucleic acid sequences. [0015] The invention further provides in another aspect an expression vector comprising the afore-mentioned isolated nucleic acid molecule, preferably operably linked to a promoter, and host cells transformed or transfected with the expression vectors. [0016] In another aspect, the invention provides a method for preventing or treating a disorder characterized by ErbB2 overexpression. The method can be used to prevent the disorder in a subject at risk of developing the disorder or, alternatively, to treat the disorder in a subject having the disorder. In embodiments of either, the methods further comprise first selecting a subject to be treated (e.g., a subject having the disorder or a subject at risk of developing the disorder). [0017] In another aspect, a pharmaceutical preparation is provided comprising one or a combination of the afore-mentioned compositions and a pharmaceutically acceptable carrier. The pharmaceutical preparation and compositions may be in a sustained release vehicle. [0018] The method comprises administering to a subject in need of such treatment an ErbB2 binding peptide that binds to an extracellular domain of ErbB2, and preferably inhibits phosphorylation of ErbB2. In some important embodiments, the ErbB2 binding peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38 and SEQ ID NO:39, inclusive, or functional equivalents thereof. Functional equivalents thereof include fragments of the peptide that are capable of binding specifically to the extracellular domain of ErbB2. In some embodiments, the EBP or functional equivalent thereof is administered in an amount effective to inhibit the disorder. In other embodiments, the method involves co-administering an anti-cancer agent to the subject. In these latter embodiments, the peptide and the anti-cancer agent are co-administered in a combined effective amount to inhibit the disorder. In related aspects of the foregoing methods non-peptide small molecules that functionally and/or structurally mimic the EBP of the invention can also be used in place of the EBPs. [0019] In one embodiment, the disorder is in or is likely to be in a tissue selected from the group consisting of the breast, ovary, uterus, cervix, thyroid gland, gastrointestinal tissue, colon, stomach, lung and bladder. In important embodiments, the disorder is a cancer. The cancer may be a primary tumor or a metastasis. The cancer may be selected from the group consisting of breast cancer, ovarian cancer (including endometrioid carcinoma), Ewing's sarcoma, cervical cancer, colorectal cancer (e.g., colorectal adenomas and adenocarcinomas), thyroid cancer, lung cancer, prostate cancer, stomach cancer, and bladder cancer. [0020] In one embodiment, the peptide is administered systemically. In another embodiment, the peptide is administered locally. In yet another embodiment, the peptide is administered in a plurality of administrations. In another embodiment, the method further comprises administering to the subject an anti-cancer agent. [0021] The invention further provides a method for inhibiting a metastasis (e.g., preventing tumor cell metastasis) by administering to a subject in need of such treatment one or a combination of any of the above-identified peptides or functional equivalents in an amount effective to prevent the formation or development of a metastasis. The metastasis may be present in bone marrow, lung, brain, and liver, but is not so limited. Continue reading... Full patent description for Binding peptides specific for the extracellular domain of erbb2 and uses therefor Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Binding peptides specific for the extracellular domain of erbb2 and uses therefor patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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