Thrombospondin-1 polypeptides and methods of using same

a technology of thrombospondin and polypeptides, applied in the field of thrombospondin-1 polypeptides, can solve the problems of poor survival/incidence ratio, and achieve the effect of reducing the size of primary tumors

Inactive Publication Date: 2014-09-18
BETH ISRAEL DEACONESS MEDICAL CENT INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0029]The “CH2 domain” of a human IgG Fc region usually extends from about residues 231 to about 340 of the IgG. The CH2 domain is unique in that it is not closely paired with another domain. Rather, two N-linked branched carbohydrate chains are interposed between the two CH2 domains of an intact native IgG molecule. It has been speculated that the carbohydrate may provide a substitute for the domain-domain pairing and help stabilize the CH2 domain (Burton. Molec. Immunol. 22: 161-206, 1985).

Problems solved by technology

The poor ratio of survival to incidence in EOC is related to the high percentage of cases that are diagnosed at an advanced stage and the lack of effective therapies for advanced refractory disease.

Method used

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  • Thrombospondin-1 polypeptides and methods of using same
  • Thrombospondin-1 polypeptides and methods of using same
  • Thrombospondin-1 polypeptides and methods of using same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Materials and Methods

Mouse Model of Epithelial Ovarian Cancer (EOC)

[0158]All animals were housed and treated in accordance with the Canadian Council on Animal Care. Tumor induction was done as described previously (Greenaway et al. Gynecol. Oncol. 121: 532-545, 2007; Greenaway et al. Mol. Cancer Ther. 8: 64-74, 2009). Briefly, 106 spontaneously transformed mouse epithelial cells (ID8) were suspended in 5 μL PBS and orthotopically injected under the ovarian bursa of anesthetized syngeneic C57BL / 6 mice using a Hamilton syringe (Fisher) and a 30-gauge needle. The contralateral ovary received an injection of 5 μL PBS under the ovarian bursa. Mice were then divided into treatment groups (e.g., 3TSR treatment or control treatment groups).

[0159]In this mouse model of EOC, mice develop a distinct primary ovarian tumor by approximately 60 days post tumor induction (PTI), which replicates Stage II EOC in women. By 80 days, mice exhibit signs similar to women with Stage III EOC, with dissemina...

example 2

3TSR is a Potent Inhibitor of Epithelial Ovarian Cancer (EOC) Growth In Vitro

[0163]We have found that treatment of murine ovarian surface epithelial (ID8) cells with 3 μM 3TSR in vitro results in a 10-fold increase in apoptosis and a 5-fold decrease in proliferation. ID8 cells were cultured in presence or absence of 3TSR (3 μM) for 24 hours. As depicted in FIG. 1, 3TSR significantly (pMod. Pathol. 21: 1002-1010, 2008). In addition, CD36 is expressed in EOC cells isolated from patient ascites (R. Watnick and R. Drapkin, personal communication).

example 3

3TSR is a Potent Inhibitor of Epithelial Ovarian Cancer (EOC) Growth In Vivo

[0164]We have recently found that 3TSR is particularly active in an orthotopic model of epithelial ovarian cancer (EOC). When 3TSR was used as a single agent and treatment was initiated at advanced stages of disease, mice showed tumor regression and greatly increased survival.

[0165]In an intervention trial with the orthotopic model, ovarian tumors were allowed to develop untreated for 80 days post tumor induction (PTI), at which time the mice have large primary tumors, numerous peritoneal metastases and the beginning of hemorrhagic ascites. Treatment with 3TSR for 20 days, as a single agent, induced significant (p<0.5) regression of advanced stage EOC compared to control treatment with PBS by reducing primary tumor weight (FIG. 3) and size (FIG. 4) as well as completely eradicating metastatic peritoneal tumors and ascites, which account for the majority of morbidity and mortality associated with EOC.

[0166]Al...

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Abstract

The invention features thrombospondin-1 (TSP-1) polypeptides (e.g., 3TSR-Fc fusion proteins), nucleic acid molecules encoding the TSP-1 polypeptides, and compositions thereof. The invention also features methods of making and using the TSP-1 polypeptides of the invention (e.g., using 3TSR-Fc fusion proteins to treat a subject having a disorder associated with pathological angiogenesis, e.g., cancer, e.g., epithelial ovarian cancer (EOC)).

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of the filing date of U.S. Provisional Application No. 61 / 782,136, filed Mar. 14, 2013, herein incorporated by reference in its entirety.STATEMENT AS TO FEDERALLY FUNDED RESEARCH[0002]This invention was made with government support under Grant No. CA130895, awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Thrombospondin-1 (TSP-1) is a potent endogenous inhibitor of tumor growth and angiogenesis. It inhibits endothelial cell growth, migration, and tube formation in vitro. In vitro assays have shown that platelet TSP-1 is involved in thrombosis, fibrinolysis, wound healing, inflammation, tumor cell metastasis, and angiogenesis. TSP-1 is the major form of thrombospondin secreted by platelets and endothelial cells.[0004]The in-growth of new capillary networks into developing tumors is essential for the progression of cance...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/47C07K16/18
CPCC07K16/18C07K14/4703C07K14/78A61K47/68C07K16/00C07K2319/30
Inventor LAWLER, JOHN W.DUQUETTE, MARKPETRIK, JAMES
Owner BETH ISRAEL DEACONESS MEDICAL CENT INC
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