Beta-2-glycoprotein 1 is an inhibitor of angiogenesis

Abstract

The present disclosure provides a method of inhibiting angiogenesis within a tissue of interest by providing either intact or nicked β2-Glycoprotein 1 (βGP1) to cells associated with the tissue. The presence of β2GP1 inhibits angiogenesis within the tissue, in part by preventing neovascularization into the tissue. The disclosure also provides a method for treating tumors by providing β2GP1 to the tumor.

1 . A method of inhibiting angiogenesis within a tissue at a site in a subject having an angiogenic disease, comprising administering an effective amount of a β2GP1 polypeptide to cells associated with the tissue in said subject, wherein said β2GP1 polypeptide is β2GP1 domain I, β2GP1 domain II, β2GP1 domain III, β2GP1 domain IV, β2GP1 domain V, β2GP1 domains I through IV, β2GP1 domains II through V, β2GP1 domains III through V, or β2GP1 domains IV and V, and wherein the amount is effective to inhibit angiogenesis within the tissue. 
     
     
         2 . The method of  claim 1 , wherein said β2GP1 polypeptide is β2GP1 domain I. 
     
     
         3 . The method of  claim 1 , wherein said β2GP1 polypeptide is β2GP1 domain II. 
     
     
         4 . The method of  claim 1 , wherein the β2GP1 polypeptide is β2GP1 domain III. 
     
     
         5 . The method of  claim 1 , wherein the β2GP1 polypeptide is β2GP1 domain IV. 
     
     
         6 . The method of  claim 1 , wherein the β32GP1 polypeptide is β2GP1 domain V. 
     
     
         7 . The method of  claim 1 , wherein the cells associated with the tissue are vascular endothelial cells. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the tissue is a tumor. 
     
     
         10 . The method of  claim 9 , wherein said method further inhibits neovascularization into the tumor. 
     
     
         11 . The method of  claim 1 , further comprising administering an antiangiogenic agent to the cells in conjunction with said β2GP1 polypeptide. 
     
     
         12 . The method of  claim 11 , wherein the antiangiogenic agent is selected from the group consisting of angiostatin, endostatin, trastuzumab, thrombospondin, IFN-α, TIMP-1, PF4, fumagillin, a tyrosine kinase inhibitor, an antibody to VEGF, and mixtures thereof. 
     
     
         13 . The method of  claim 45 , wherein the β2GP1 polypeptide is supplied to the eye topically. 
     
     
         14 . A method of inhibiting endothelial cell proliferation, comprising administering an effective amount of a β2GP1 polypeptide to the endothelial cells, wherein said β2GP1 polypeptide is β2GP1 domain I, β2GP1 domain II, β2GP1 domain III, β2GP1 domain IV, β2GP1 domain V, β2GP1 domains I through IV, β2GP1 domains II through V, β2GP1 domains III through V, or β2GP1 domains IV and V, and wherein the amount is effective to inhibit endothelial cell proliferation. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 14 , wherein said method further inhibits endothelial cell migration. 
     
     
         18 . The method of  claim 14 , wherein said method further inhibits endothelial cell differentiation. 
     
     
         19 . The method of  claim 18 , wherein the endothelial cells are inhibited from differentiating into tubular capillary structures. 
     
     
         20 . The method of  claim 1 , wherein the tissue is a neoplasm. 
     
     
         21 . The method of  claim 1 , wherein said β2GP1 polypeptide is β2GP1 domains I through IV. 
     
     
         22 . The method of  claim 1 , wherein said β2GP1 polypeptide is β2GP1 domains II through V. 
     
     
         23 . The method of  claim 1 , wherein the β2GP1 polypeptide is β2GP1 domains III through V. 
     
     
         24 . The method of  claim 1 , wherein the β2GP1 polypeptide is β2GP1 domains IV and V. 
     
     
         25 . The method of  claim 9 , wherein said method further inhibits metastasis of the tumor. 
     
     
         26 .- 29 . (canceled) 
     
     
         30 . The method of  claim 9 , further comprising administering a therapeutic agent useful in the treatment of the tumor in conjunction with said β2GP1 polypeptide. 
     
     
         31 . The method of  claim 30 , wherein the therapeutic agent is selected from the group consisting of cisplatin, doxorubicin, paclitaxel, vincristine, tamoxifen, taxotere, methotrexate, carboplatin and vinblastine. 
     
     
         32 .- 34 . (canceled) 
     
     
         35 . The method of  claim 1 , wherein the subject is human. 
     
     
         36 . The method of  claim 1 , wherein the β2GP1 polypeptide is β2GP1 domain V, β2GP1 domains II through V, β2GP1 domains III through V, or β2GP1 domains IV and V. 
     
     
         37 . The method of  claim 36 , wherein the β2GP1 domain V is nicked β2GP1 domain V (N-β2GP1 domain V). 
     
     
         38 . The method of  claim 1 , wherein the route of administration to the subject is oral, intravenous, intramuscular, intrathecal, intradermal, intraperitoneal, subcutaneous, intrapleural, intrauterine, rectal, vaginal, intratumor, transdermal, or transmucosal. 
     
     
         39 .- 43 . (canceled) 
     
     
         44 . The method of  claim 1 , wherein said angiogenic disease is an angiogenic disease of the eve, skin, joints, gastrointestinal tract, reproductive system, or involved with fracture or wound healing. 
     
     
         45 . The method of  claim 44 , wherein said angiogenic disease is an angiogenic disease of the eye. 
     
     
         46 . The method of  claim 44 , wherein said angiogenic disease is an angiogenic disease of the skin. 
     
     
         47 . The method of  claim 44 , wherein said angiogenic disease is an angiogenic disease of the joints. 
     
     
         48 . The method of  claim 44 , wherein the angiogenic disease is an angiogenic disease of the gastrointestinal tract. 
     
     
         49 . The method of  claim 45 , wherein the angiogenic disease is a corneal disease, hypoxia, infection, diabetic retinopathy, retrolental fibroplasia, trachoma, neovascular glaucoma, rubeosis, macular degeneration or an angiogenic disease associated with an eye injury or laser surgery. 
     
     
         50 . The method of  claim 1 , wherein the site is dermis, epidermis, endometrium, retina, surgical wound, gastrointestinal tract, umbilical cord, liver, kidney, reproductive system, lymphoid system, central nervous system, breast tissue, urinary tract, bone, muscle, or respiratory tract. 
     
     
         51 . A pharmaceutical composition comprising a β2GP1 polypeptide and a second antiangiogenic agent useful for the inhibition of angiogenesis; wherein said β2GP1 polypeptide is β2GP1 domain I, β2GP1 domain II, β2GP1 domain III, β2GP1 domain IV, β2GP1 domain V, β2GP1 domains I through IV, β2GP1 domains II through V, 02GP1 domains III through V, or β2GP1 domains IV and V. 
     
     
         52 . (canceled) 
     
     
         53 . (canceled) 
     
     
         54 . The composition of  claim 51 , wherein the second antiangiogenic agent is selected from the group consisting of angiostatin, endostatin, trastuzumab, thrombospondin, IFN-α, TIMP-1, PF4, a tyrosine kinase inhibitor, an antibody to VEGF, and fumagillin. 
     
     
         55 . A pharmaceutical composition comprising a β2GP1 polypeptide and a second therapeutic agent; wherein said β2GP1 polypeptide is β2GP1 domain I, β2GP1 domain II, β2GP1 domain III, β2GP1 domain IV, β2GP1 domain V, β2GP1 domains I through IV, β2GP1 domains II through V, β2GP1 domains III through V, or β2GP1 domains IV and V, and wherein said second therapeutic agent is useful for the treatment of a neoplasm. 
     
     
         56 . (canceled) 
     
     
         57 . (canceled) 
     
     
         58 . The composition of  claim 55 , wherein the second therapeutic agent is selected from the group consisting of cisplatin, doxorubicin, paclitaxel, vincristine tamoxifen, taxotere, methotrexate, carboplatin and vinblastine. 
     
     
         59 . The method of  claim 46 , wherein the angiogenic disease is psoriasis, scleroderma, neovascularization as a consequence of infection, cat scratch disease, bacterial ulceration, lupus erythematosus, telangiectasia, or hypertrophic scars. 
     
     
         60 . The method of  claim 47 , wherein the angiogenic disease is arthritis, rheumatoid arthritis, hemophiliac joints, lupus erythematosus, immune-inflammation, or non-immune inflammation. 
     
     
         61 . The method of  claim 48 , wherein the angiogenic disease is angioectasia, telangiectasia, intestinal adhesions, Crohn's disease, Oster-Webber Syndrome, or peptic ulcer. 
     
     
         62 . The method of  claim 44 , wherein the angiogenic disease is an angiogenic disease associated with a fracture or would healing. 
     
     
         63 . The method of  claim 62 , wherein the angiogenic disease is associated with excessive wound repair, wound granularization, or an ischemic limb.