Project 1. Targeted Radiotherapy of Neoplastic Meningitis using Monoclonal Antibodies Labeled with Alpha Particle Emitting [211] At. Michael Zaiutsky, Ph.D., Project Leader Neoplastic meningitis (NM), characterized by the dissemination of malignant tumor cells within the leptomeningeal space and metastatic spread along the brain and spine, is a devestating disease resulting in a median survival of only 2-6 months. In terms of number of patients affected, breast and lung carcinoma are the most common primary sites that metastasize to the leptomeninges. We propose to focus initially on the rapid translational development of a targeted radiotherapeutic for breast carcinoma NM and if successful, apply the same approach to lung carcinoma. Our strategy is to combine trastuzumab with the a-particle emitter ^^^At because these a-particles have a greater cytotoxic effectiveness than conventional radiation and have a range in tissue of only a few cell diameters, characteristics that offer important advantages for NM treatment. We seek to determine the best method for labeling trastuzumab not only for[211]At but also for [124] l to move fonward to clinical investigation. If we can establish similar in vivo behavior for mAb labeled via the two radiohalogens, PET imaging with [124] l-labeled trastuzumab could provide a valuable tool for determining radiation dosimetry, evaluating distribution within the neuroaxis, and individualizing patient treatment protocols for [211]At-labeled trastuzumab.
Our Specific Aims are: 1) To label trastuzumab with [211]At and [124] l using methodologies designed to minimize dehalogenation and maximize entrapment of radioactivity within tumor cells after labeled mAb internalization;2) to evaluate these radiolabeled trastuzumab conjugates in human breast carcinoma cells in vitro, and tissue distribution in mice with subcutaneous breast carcinoma xenografts and in an athymic rat NM model of HER2 expressing breast carcinoma;3) to determine the therapeutic efficacy, neuroaxis distribution, toxicity, and radiation dosimetry in athymic rat models of NM;4) To obtain FDA Investigational New Drug permits for the best [211] At- and [124] l-labeled trastuzumab conjugates, and then to conduct clinical trials in patients with breast carcinoma NM and 5) Using the same translational paradigm determine the best strategy for labeling panitumumab with [211]At and [124] I and evaluate their potential as targeted radiotherapeutics and diagnostics for patients with lung carcinoma NM.

Public Health Relevance

Neoplastic meningitis is a devastating disease characterized by the spread of malignant tumor cells through-out the cerebrospinal fluid compartment, along the brain and spine, for which there is no effective treatment. Using highly radioactive antibodies, we seek to be able to treat this disease in breast and lung cancer patients without the debilitating side effects that are associated with current therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA154291-01A1
Application #
8236380
Study Section
Special Emphasis Panel (ZCA1-GRB-P (O1))
Project Start
2012-07-11
Project End
2017-06-30
Budget Start
2012-07-11
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$344,787
Indirect Cost
$124,344
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Bao, Xuhui; Chandramohan, Vidyalakshmi; Reynolds, Randall P et al. (2016) Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats. Invest New Drugs 34:149-58
Suryadevara, Carter M; Riccione, Katherine A; Sampson, John H (2016) Immunotherapy Gone Viral: Bortezomib and oHSV Enhance Antitumor NK-Cell Activity. Clin Cancer Res 22:5164-5166
Saraswathula, Anirudh; Reap, Elizabeth A; Choi, Bryan D et al. (2016) Serum elevation of B lymphocyte stimulator does not increase regulatory B cells in glioblastoma patients undergoing immunotherapy. Cancer Immunol Immunother 65:205-11
Mitchell, Duane A; Batich, Kristen A; Gunn, Michael D et al. (2015) Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519:366-9
Pruszyński, Marek; Łyczko, Monika; Bilewicz, Aleksander et al. (2015) Stability and in vivo behavior of Rh[16aneS4-diol]211 at complex: a potential precursor for astatine radiopharmaceuticals. Nucl Med Biol 42:439-45
Huang, Dong-Sheng; Wang, Zhaohui; He, Xu-Jun et al. (2015) Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation. Eur J Cancer 51:969-76
Pruszynski, Marek; Koumarianou, Eftychia; Vaidyanathan, Ganesan et al. (2015) D-Amino acid peptide residualizing agents bearing N-hydroxysuccinimido- and maleimido-functional groups and their application for trastuzumab radioiodination. Nucl Med Biol 42:19-27
Pruszynski, Marek; Koumarianou, Eftychia; Vaidyanathan, Ganesan et al. (2014) Improved tumor targeting of anti-HER2 nanobody through N-succinimidyl 4-guanidinomethyl-3-iodobenzoate radiolabeling. J Nucl Med 55:650-6
Choi, Jaeyeon; Vaidyanathan, Ganesan; Koumarianou, Eftychia et al. (2014) N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: influence of isomeric substitution on radiolabeling and target cell residualization. Nucl Med Biol 41:802-12
Congdon, Kendra L; Gedeon, Patrick C; Suryadevara, Carter M et al. (2014) Epidermal growth factor receptor and variant III targeted immunotherapy. Neuro Oncol 16 Suppl 8:viii20-5

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