publications & abstracts

product pipeline | publications & abstracts

Publications

Tumor Paint: A Chlorotoxin:Cy5.5 Bioconjugate for Intraoperative Visualization of Cancer Foci.
Veiseh M, Gabikian P, Bahrami S, et al. Cancer Res. 2007;64(14):6882-6888.

To access the journal article abstract, click here.

Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601)
Adam N Mamelak†1 & Douglas B Jacoby2

1Attending Neurosurgeon, Cedars-Sinai Medical Center, Maxine Dunitz Neurosurgical Institute, Department of Neurosurgery, Los Angeles, CA8631 W. Third Street, Suite 800e, Los Angeles, CA 90048, USA. mamelaka@cshs.org

2Senior Director of Research, TransMolecular, Inc., Cambridge, MA, US

† Author for correspondence

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Phase I Single-Dose Study of Intracavitary-Administered Iodine-131TM-601 in Adults With Recurrent High-Grade Glioma
Mamelak AN, Rosenfeld S, Buscholz R, et al. J Clin Oncol, Vol 24, No 22 (August 1), 2006: pp. 3644-3650

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Imaging Glioma Extent with I-TM-601

David C. Hockaday, BS1; Sui Shen, PhD2; John Fiveash, MD2; Andrew Raubitschek, MD3; David Colcher, PhD3; An Liu, PhD3; Vern Alvarez, PhD4; and Adam N. Mamelak, MD1. J Mucl Med. 2005:46:580-586.

TM-601, a 36-amino-acid peptide, selectively binds to glioma cells but not normal brain parenchyma. A phase I/II clinical trial of intracavitary I-TM-601 in adult patients with recurrent highgrade glioma was performed to determine the biodistribution and toxicity of this potential therapy. We evaluated imaging and biodistribution data from this trial to assess...
full article

Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin
Lyons S, O'Neal J, Sontheimer H. GLIA. 2002; 39:162-173

Abstract
Highly migratory neuroectodermal cells share a common embryonic origin with cells of the central nervous system (CNS). They include enteric, parasympathetic, sympathoadrenal, and sensory neurons of the peripheral nervous system, Schwann cells, melanocytes, endocrine cells, and cells forming connective tissue of the face and neck. Because of their common embryologic origin, these cells and the tumors that derive from them can share genetic and antigenic phenotypes with gliomas, tumors derived from CNS glia. We recently discovered that chlorotoxin (ClTx), a 4-kD peptide purified from Leiurus quinquestriatus scorpion, is a highly specific marker for glioma cells in biopsy tissues (Soroceanu et al. Cancer Res 58:4871-4879, [1998]) that can target tumors in animal models. We report on the specificity of ClTx as a marker for tumors of neuroectodermal origin that include peripheral neuroectodermal tumors (PNET) and gliomas. Specifically, we histochemically stained frozen and paraffin tissue sections of human biopsy tissues from 262 patients with a synthetically manufactured and biologically active ClTx bearing an N-terminal biotin. The vast majority (74 of 79) of primary human brain tumors investigated showed abundant binding of ClTx with greater than 90% ClTx-positive cells in each section. By comparison, 32 biopsies of uninvolved brain used for comparison were largely ClTx-negative, with only a few isolated reactive astrocytes showing some ClTx binding. However, as with gliomas, the vast majority of PNETs examined showed specific ClTx binding (31 of 34). These include medulloblastomas (4 of 4), neuroblastomas (6 of 7), ganglioneuromas (4 of 4), melanomas (7 of 7), adrenal pheochromocytomas (5 of 6), primitive PNET (1), small cell lung carcinoma (2 of 3), and Ewing's sarcoma (2 of 2). Under identical staining conditions, normal tissues from brain, skin, kidney, and lung were consistently negative for ClTx. These results suggest that chlorotoxin is a reliable and specific histopathological marker for tumors of neuroectodermal origin and that chlorotoxin derivatives with cytolytic activity may have therapeutic potential for these cancers.

Direct Interaction with Contactin Targets Voltage-gated Sodium Channel Nav1.9/NaN to the Cell Membrane
Liu C, Dib-Hajj S, Black J, Greenwood J, Lian Z, Waxman S. J Biological Chem. 2001; Vol. 276, No. 49, Issue of December 7, pp. 46553-46561

Abstract
The mechanisms that target various sodium channels within different regions of the neuronal membrane, which they endow with different physiological properties, are not yet understood. To examine this issue we studied the voltage-gated sodium channel Nav1.9/NaN, which is preferentially expressed in small sensory neurons of dorsal root ganglia and trigeminal ganglia and the nonmyelinated axons that arise from them. Our results show that the cell adhesion molecule contactin binds directly to Nav1.9/NaN and recruits tenascin to the protein complex in vitro. Nav1.9/NaN and contactin co-immunoprecipitate from dorsal root ganglia and transfected Chinese hamster ovary cell line, and co-localize in the C-type neuron soma and along nonmyelinated C-fibers and at nerve endings in the skin. Co-transfection of Chinese hamster ovary cells with Nav1.9/NaN and contactin enhances the surface expression of the sodium channel over that of Nav1.9/NaN alone. Thus contactin binds directly to Nav1.9/NaN and participates in the surface localization of this channel along nonmyelinated axons.

Abstracts

Safety and tolerance of multiple weekly intracavitary injections of I-chlorotoxin (TM-601): Preliminary results of a prospective clinical trial in patients with recurrent glioblastoma multiforme.
Abstract No:1555

J. B. Fiveash, L. B. Nabors, A. N. Mamelak, N. G. Avgeropoulos, B. L. Guthrie, N. W. Salomon, J. Portnow, R. D. Bucholz. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 1555

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“Reprinted with permission from the American Society of Clnical Oncology”

A Phase I/II Clinical Trial for Adult Recurrent Glioma Using I-TM-601, an Iodinated Peptide Derived from Scorpion Venom Which Targets a Receptor Found on Tumor Cells

V. L. Alvarez, Ph.D., A. Mamelak, MD, A. Raubitschek, S. Rosenfeld, MD, Ph.D., B. Nabors MD, J. B. Fiveash, M.D, .M. B. Khazaeli, Ph.D., S. Shen, Ph.D., R. Bucholz MD, D. Hablitz, MSN, and M. A. Gonda, Ph.D.. TransMolecular, Inc., Birmingham, AL, City of Hope, Duarte, CA, 3University of Alabama at Birmingham, Birmingham, AL, and St. Louis University School of Medicine, St. Louis, MO. Presented at the Advances in the Application of Monoclonal Antibodies in Clinical Oncology Conference, Anassa Hotel, Latchi, Cyprus June 30th – July 2nd, 2003

Introduction: I-TM-601 is radiopharmaceutical that combines a 36-amino acid peptide, called chlorotoxin (designated TM-601), derived from scorpion venom with a medicinal isotope of iodine (I). TM-601 binds a receptor found on the surface of tumor cells, which is not found on normal cells. TM-601 binds many solid tumors types including glioma, breast, lung, prostate, and melanoma. No toxicities have been observed with the administration of TM-601 to rodents or primates. Its small size permits it to diffuse through tissues and across the blood brain barrier. A single dose of I-TM-601 administered intracranially to human xenografted mouse models of glioma has been shown to extend survival up to 269% in multiple studies. In addition to specific targeting, TM-601 sequences also have properties of pharmaceutical enhancers and cytostatic agents.

Materials and Methods: I-TM-601 is currently being investigated in a multi-center phase I/II clinical trial for adult recurrent glioma. There will be a total of 18 patients, six in each of three dosing panels (10mCi/250µg 10mCi/500µg, and 10mCi/1000µg). Recurrent glioma patients have a ventricular access device (VAD) placed in the tumor cavity at the time of resection. 14 to 28 days later, a single dose of a 2 ml solution of I-TM-601is administered over a five min period via the VAD. Gamma camera, SPECT, and MRI/CT scans are taken over a six to eight day period of time. The primary endpoints are safety, toxicity, dosimetry, biodistribution and imaging and the secondary endpoints are tumor response and survival. Patients are being followed for six months or until death.

Results and Discussion: Enrollment in the first and second dosing panels is complete; as of April 2003, eleven patients have been treated with I-TM-601 at three clinical sites and with very similar results. No dose limiting toxicity directly related to drug administration has been observed. Specific targeting of residual tumor in the cavity has been demonstrated by gamma camera imaging and fused SPECT/MRI or CT scans. Between one to 10% of the radiation delivered specifically binds the tumor cavity. Biodis-tribution and dosimetry data indicate that targeting of I-TM-601 to the tumor cavity is very high and to critical organs very low. By 72 hours, 90% of the radiation has been eliminated from the body in the urine.

Conclusions: A single dose of I-TM-601appears to be safe, well tolerated, and to target tumor cells with high specificity. A phase II clinical trial for adult recurrent glioma, using multiple doses of I-TM-601 that incorporate a higher dose of radiation, is planned.