Inhibition of Placenta Growth Factor (PLGF) Mediated Metastasis and/or Angiogenesis

Abstract

The present invention concerns methods and compositions for inhibiting angiogenesis and/or tumor growth, survival and/or metastasis. In particular embodiments, the methods and compositions may concern ligands against placenta growth factor (PlGF), such as BP-1, BP-2, BP-3 or BP-4. Some methods may comprise administering one or more PlGF ligands, alone or in combination with one or more other agents, such as chemotherapeutic agents, other anti-angiogenic agents, immunotherapeutic agents or radioimmunotherapeutic agents to a subject. The PlGF ligands are effective to inhibit angiogenesis, tumor cell motility, tumor metastasis, tumor growth and/or tumor survival. In certain embodiments, PlGF ligands may be administered to subjects to ameliorate other angiogenesis related conditions, such as macular degeneration. In some embodiments, PlGF expression levels may be determined by any known method to select those patients most likely to respond to PlGF targeted therapies.

1 . A peptide having one or more functional characteristics selected from the group consisting of:
 a) the peptide binds to both PlGF and Flt-1 (Fms-like tyrosine kinase receptor);   b) the peptide binds to the heparin binding sites on PlGF-2 and Flt-1;   c) the peptide inhibits heparin binding to PlGF and/or Flt-1; and   d) heparin inhibits binding of the peptide to PlGF and/or Flt-1.   
     
     
         2 . The peptide of  claim 1 , wherein the peptide has each of the functional characteristics of (a) through (d). 
     
     
         3 . The peptide of  claim 1 , wherein the peptide inhibits angiogenesis, tumor growth or tumor metastasis. 
     
     
         4 . The peptide of  claim 3 , wherein the tumor is a breast cancer. 
     
     
         5 . The peptide of  claim 3 , wherein the tumor is selected from the group consisting of a lymphoma, a leukemia, a myeloma, a sarcoma, a glioma, a melanoma and a carcinoma. 
     
     
         6 . The peptide of  claim 1 , wherein the peptide is a PlGF ligand. 
     
     
         7 . The peptide of  claim 1 , wherein the peptide comprises the amino acid sequence of BP-1 (SEQ ID NO:1), BP-2 (SEQ ID NO:2), BP-3 (SEQ ID NO:3) or BP-4 (SEQ ID NO:4). 
     
     
         8 . The peptide of  claim 3 , wherein the tumor is selected from the group consisting of acute lymphoblastic leukemia, acute myelogenous leukemia, biliary cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, lung cancer, medullary thyroid, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, glioma, melanoma, liver cancer, prostate cancer, and urinary bladder cancer. 
     
     
         9 . The peptide of  claim 1 , wherein the peptide inhibits cancer cell survival and/or motility. 
     
     
         10 . A composition comprising a peptide according to  claim 1 , wherein the peptide is attached to another molecule or compound. 
     
     
         11 . The composition of  claim 10 , wherein the peptide is attached to an antibody, bispecific antibody, antibody fragment, chimeric antibody, humanized antibody, human antibody, human antibody fragment, antibody analog, Fc fragment, Fc-binding protein, antibody-binding fusion protein, drug, prodrug, toxin, enzyme, oligonucleotide, radioisotope, immunomodulator, cytokine, hormone, binding molecule, lipid, polymer, micelle, liposome, nanoparticle, or combination thereof. 
     
     
         12 . The composition of  claim 11 , wherein the peptide is attached to a molecule that binds to a tumor antigen. 
     
     
         13 . The composition of  claim 11 , wherein the peptide is attached to a molecule that binds to a disease target. 
     
     
         14 . The composition of  claim 12 , wherein the molecule is a bispecific antibody or fragment thereof, said antibody or fragment with one binding site for a tumor-associated antigen and a second binding site for the PlGF ligand. 
     
     
         15 . The composition of  claim 13 , wherein the peptide is covalently attached to a monoclonal antibody, said monoclonal antibody with a binding site for a disease target. 
     
     
         16 . The composition of  claim 14 , wherein the bispecific antibody has a binding site for a tumor associated antigen selected from the group consisting of A3, antigen specific for A33 antibody, BrE3-antigen, CD1, CD1a, CD3, CD5, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD30, CD45, CD74, CD79a, CD80, HLA-DR, NCA95, NCA90, HCG and its subunits, CEA (CEACAM5), CEACAM6, CSAp, EGFR, EGP-1, EGP-2, Ep-CAM, Ba 733, HER2/neu, hypoxia inducible factor (HIF-1), KC4-antigen, KS-1-antigen, KS 1-4, Le-Y, macrophage inhibition factor (MIF), MAGE, MUC1, MUC2, MUC3, MUC4, PAM-4 antigen, PSA, PSMA, RS5, 5100, TAG-72, p53, tenascin, IL-6, IL-8, insulin growth factor-1 (IGF-1), Tn antigen, Thomson-Friedenreich antigens, a tumor necrosis antigen, VEGF, ED-B fibronectin, 17-1A-antigen, an angiogenesis marker, an oncogene marker and an oncogene product. 
     
     
         17 . The composition of  claim 12 , wherein the tumor is selected from the group consisting of acute lymphoblastic leukemia, acute myelogenous leukemia, biliary cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, lung cancer, medullary thyroid, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, glioma, melanoma, liver cancer, prostate cancer, and urinary bladder cancer. 
     
     
         18 . A fusion protein comprising a peptide according to  claim 1 . 
     
     
         19 . The fusion protein of  claim 18 , wherein the fusion protein further comprises a toxin, a cytokine, an enzyme, a hormone, an antibody or an antigen-binding antibody fragment. 
     
     
         20 . A kit comprising a peptide according to  claim 1  and a container.