TransMolecular Inc.

Cambridge, MA, United States

TransMolecular Inc.

Cambridge, MA, United States

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Kesavan K.,TransMolecular Inc. | Ratliff J.,TransMolecular Inc. | Johnson E.W.,TransMolecular Inc. | Dahlberg W.,TransMolecular Inc. | And 5 more authors.
Journal of Biological Chemistry | Year: 2010

TM601 is a synthetic form of chlorotoxin, a 36-amino acid peptide derived from the venom of the Israeli scorpion, Leirius quinquestriatus, initially found to specifically bind and inhibit the migration of glioma cells in culture. Subsequent studies demonstrated specific in vitro binding to additional tumor cell lines. Recently, we demonstrated that proliferating human vascular endothelial cells are the only normal cell line tested that exhibits specific binding to TM601. Here, we identify annexin A2 as a novel binding partner for TM601 in multiple human tumor cell lines and human umbilical vein endothelial cell (HUVEC). We demonstrate that the surface binding of TM601 to the pancreatic tumor cell line Panc-1 is dependent on the expression of annexin A2. Identification of annexin A2 as a binding partner for TM601 is also consistent with the anti-angiogenic effects of TM601. Annexin A2 functions in angiogenesis by binding to tissue plasminogen activator and regulating plasminogen activation on vascular endothelial cells. We demonstrate that in HUVECs, TM601 inhibits both vascular endothelial growth factor- and basic fibroblast growth factor-induced tissue plasminogen activator activation, which is required for activation of plasminogen to plasmin. Consistent with inhibition of cell surface protease activity, TM601 also inhibits platelet-derived growth factor-C induced trans-well migration of both HUVEC and U373-MG glioma cells. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Lima E Silva R.,Johns Hopkins University | Shen J.,Johns Hopkins University | Gong Y.Y.,Johns Hopkins University | Seidel C.P.,Johns Hopkins University | And 4 more authors.
Journal of Cellular Physiology | Year: 2010

TM601 is a synthetic polypeptide with sequence derived from the venom of the scorpion Leiurus quinquestriatus that has anti-neoplastic activity. It has recently been demonstrated to bind annexin A2 on cultured tumor and vascular endothelial cells and to suppress blood vessel growth on chick chorioallantoic membrane. In this study, we investigated the effects of TM601 in models of ocular neovascularization (NV). When administered by intraocular injection, intravenous injections, or periocular injections, TM601 significantly suppressed the development of choroidal NV at rupture sites in Bruch's membrane. Treatment of established choroidal NV with TM601 caused apoptosis of endothelial cells and regression of the NV. TM601 suppressed ischemia-induced and vascular endothelial growth factor-induced retinal NV and reduced excess vascular permeability induced by vascular endothelial growth factor. Immunostaining with an antibody directed against TM601 showed that after intraocular or periocular injection, TM601 selectively bound to choroidal or retinal NV and co-localized with annexin A2, which is undetectable in normal retinal and choroidal vessels, but is upregulated in endothelial cells participating in choroidal or retinal NV. Intraocular injection of plasminogen or tissue plasminogen activator, which like TM601 bind to annexin A2, also suppressed retinal NV. This study supports the hypothesis that annexin A2 is an important target for treatment of neovascular diseases and suggests that TM601, through its interaction with annexin A2, causes suppression and regression of ocular NV and reduces vascular leakage and thus may provide a new treatment for blinding diseases such as neovascular age-related macular degeneration and diabetic retinopathy. © 2010 Wiley-Liss, Inc.


Jacoby D.B.,TransMolecular Inc. | Dyskin E.,Albany College of Pharmacy and Health Sciences | Yalcin M.,Albany College of Pharmacy and Health Sciences | Kesavan K.,TransMolecular Inc. | And 4 more authors.
Anticancer Research | Year: 2010

Chemically synthesized chlorotoxin (TM601) has been studied as a tumor targeting peptide. In this study, the anti-angiogenic properties of TM601 are reported. Materials and Methods: In vitro and in vivo models of angiogenesis and tumor growth were used to characterize the anti-angiogenic effects of TM601. Results: TM601 bound to proliferating vascular endothelial cells, decreased human umbilical vein endothelial cell (HUVEC) invasion, and reduced secretion of bioactive matrix metalloproteinase-2 (MMP-2). Using the chick chorioallantoic membrane assay (CAM), TM601 inhibited angiogenesis stimulated by any of eight proangiogenic factors, and when TM601 was co-administered with bevacizumab, the combination was significantly more potent than a ten-fold increase in bevacizumab dose. TM601 did not alter tumor or vascular endothelial cell growth in vitro, but TM601 treatment of tumors grown on the CAM decreased tumor growth and intra-tumoral hemoglobin levels. Intravenously injected TM601 was also shown to significantly decrease new blood vessel growth in mice. Conclusion: TM601 inhibits angiogenesis stimulated by many factors and potentiates the anti-angiogenic effect of bevacizumab.


This invention includes compositions for combination therapy, particularly involving at least one chemotherapeutic agent used in combination with chlorotoxin or a derivative thereof.


Patent
Transmolecular Inc. | Date: 2010-04-07

This invention includes compositions and methods for combination chemotherapy, particularly involving at least one chemotherapeutic agent used in combination with chlorotoxin or a derivative thereof.


Patent
Transmolecular Inc. | Date: 2010-01-27

The present invention is directed to methods and compositions for the - treatment and diagnosis of neuroectodermally-derived tumors, such as gliomas. The inventive methods of treatment generally include local (e.g. intracavitary) administration of the chlorotoxin moiety conjugated to a cytotoxic moiety to a patient. Also provided are diagnostic methods for screening neoplastic neuroectodermal tumors.


Patent
Transmolecular inc. | Date: 2012-03-21

This invention includes compositions for combination therapy, particularly involving at least one chemotherapeutic agent used in combination with chlorotoxin or a derivative thereof.


PubMed | TransMolecular Inc.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

9556 Background: Tumor formation requires altered motility of transforming cells to invade surrounding tissues. This altered cellular motility involves formation of lamellipodia, protrusions of the plasma membrane at the leading edge of the cell. Recent studies establish a role for phosphatidylinositol-3-kinase (PI3K) and the PI3K/Akt pathway in initiation of membrane ruffling and actin stress fiber formation, events necessary for lamellipodia formation. PI3K regulates the membrane phospholipids PI(4,5)PWe investigated the mechanism of action of TM-601, a synthetic peptide derivative of scorpion venom, in human cancer cells. Multiple established human cancer cell lines were used in these studies, including solid tumor (glioblastoma, prostate, breast, lung, melanoma, colon) and hematologic tumor cell lines (lymphoma, leukemia, myeloma). Histochemical staining, FACS analysis, and in vitro binding assays were used to characterize TM-601 binding, identify specific intracellular targets, and investigate downstream effects.TM-601 bound all cancer cell lines tested and histological staining localized binding to the lamellipodia of cancer cells. Using in vitro binding assays, we identified phosphatidylinositol-4,5-bisphosphate (PI(4,5)PTM-601 is a novel 36 amino-acid peptide that targets human cancer cells via a phosphatidylinositol phosphate resulting in altered activity of the PI3K/Akt signal transduction pathway.


PubMed | TransMolecular Inc.
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2010

TM601 is a synthetic form of chlorotoxin, a 36-amino acid peptide derived from the venom of the Israeli scorpion, Leirius quinquestriatus, initially found to specifically bind and inhibit the migration of glioma cells in culture. Subsequent studies demonstrated specific in vitro binding to additional tumor cell lines. Recently, we demonstrated that proliferating human vascular endothelial cells are the only normal cell line tested that exhibits specific binding to TM601. Here, we identify annexin A2 as a novel binding partner for TM601 in multiple human tumor cell lines and human umbilical vein endothelial cell (HUVEC). We demonstrate that the surface binding of TM601 to the pancreatic tumor cell line Panc-1 is dependent on the expression of annexin A2. Identification of annexin A2 as a binding partner for TM601 is also consistent with the anti-angiogenic effects of TM601. Annexin A2 functions in angiogenesis by binding to tissue plasminogen activator and regulating plasminogen activation on vascular endothelial cells. We demonstrate that in HUVECs, TM601 inhibits both vascular endothelial growth factor- and basic fibroblast growth factor-induced tissue plasminogen activator activation, which is required for activation of plasminogen to plasmin. Consistent with inhibition of cell surface protease activity, TM601 also inhibits platelet-derived growth factor-C induced trans-well migration of both HUVEC and U373-MG glioma cells.


PubMed | TransMolecular Inc.
Type: Journal Article | Journal: Anticancer research | Year: 2010

Chemically synthesized chlorotoxin (TM601) has been studied as a tumor targeting peptide. In this study, the anti-angiogenic properties of TM601 are reported.In vitro and in vivo models of angiogenesis and tumor growth were used to characterize the anti-angiogenic effects of TM601.TM601 bound to proliferating vascular endothelial cells, decreased human umbilical vein endothelial cell (HUVEC) invasion, and reduced secretion of bioactive matrix metalloproteinase-2 (MMP-2). Using the chick chorioallantoic membrane assay (CAM), TM601 inhibited angiogenesis stimulated by any of eight pro-angiogenic factors, and when TM601 was co-administered with bevacizumab, the combination was significantly more potent than a ten-fold increase in bevacizumab dose. TM601 did not alter tumor or vascular endothelial cell growth in vitro, but TM601 treatment of tumors grown on the CAM decreased tumor growth and intra-tumoral hemoglobin levels. Intravenously injected TM601 was also shown to significantly decrease new blood vessel growth in mice.TM601 inhibits angiogenesis stimulated by many factors and potentiates the anti-angiogenic effect of bevacizumab.

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