Antibody-targeted radiation therapy (Radioimmunotherapy, RIT) has shown great promise in the treatment of various cancers as demonstrated by numerous clinical and preclinical studies. The first FDA-approved RIT drug, Zevalin(R), containing Y-90 (beta particle-emitting radionuclide), 1B4M-DTPA (bifunctional ligand), and Rituximab (anti-CD20 antibody) significantly enhanced the overall response rate in the treatment of non- Hodgkin's lymphoma (NHL) as compared to anti-CD20 therapy alone. The alpha- or beta-emitting radionuclides, Y-90, Lu-177, Bi-213, Pb-212, and Ac-225 are effective cytotoxic agents and have been investigated for RIT of cancers including leukemia and lymphoma and micrometastatic tumors. To minimize radiotoxicity and enhance potency of RIT, a bifunctional ligand that can effectively sequester the radionuclide must be employed. Absence of effective bifunctional ligands for the radionuclides remains a limitation in active clinical exploration of RIT. The objective of this investigation is to develop highly effective bifunctional ligands for RIT using Y-90, Lu-177, Bi-213, Pb-212, and Ac-225. The hypothesis of this study is that the new bimodal bifunctional ligands with both macrocyclic and acyclic binding moieties will rapidly form highly stable complexes with Y-90, Lu-177, Bi-213, Pb-212, and Ac-225.
The specific aims of this study are i) synthesis and chemical evaluation of the novel bimodal bifunctional ligands;ii) conjugation of the ligands to a tumor-targeting antibody, Herceptin or Panitumumab, and evaluation of the corresponding ligand-antibody conjugates for radiolabeling kinetics and serum stability with Y-90, Lu-177, Bi-213, Pb-212, and Ac-225;iii) biodistribution, pharmacokinetics and dosimetry studies of Y-90, Lu-177, Bi-213, Pb-212, and Ac-225-radiolabeled antibody conjugates in colon cancer-bearing mice;iv) therapy and toxicity studies of the radiolabeled antibody conjugates. The proposed research will lead to the development of superior chelation chemistry that allows for practical preparation of less toxic and more potent RIT drugs for cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Therapeutics and Biology Study Section (RTB)
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Capala, Jacek
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Illinois Institute of Technology
Other Basic Sciences
Schools of Arts and Sciences
United States
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Kang, Chi Soo; Song, Hyun A; Milenic, Diane E et al. (2013) Preclinical evaluation of NETA-based bifunctional ligand for radioimmunotherapy applications using 212Bi and 213Bi: radiolabeling, serum stability, and biodistribution and tumor uptake studies. Nucl Med Biol 40:600-5
Chong, Hyun-Soon; Song, Hyun A; Kang, Chi Soo et al. (2011) A highly effective bifunctional ligand for radioimmunotherapy applications. Chem Commun (Camb) 47:5584-6
Dadwal, Mamta; Kang, Chi Soo; Song, Hyun A et al. (2011) Synthesis and evaluation of a bifunctional chelate for development of Bi(III)-labeled radioimmunoconjugates. Bioorg Med Chem Lett 21:7513-5
Song, Hyun A; Kang, Chi Soo; Baidoo, Kwamena E et al. (2011) Efficient bifunctional decadentate ligand 3p-C-DEPA for targeted ?-radioimmunotherapy applications. Bioconjug Chem 22:1128-35
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Chong, Hyun-Soon; Lim, Sooyoun; Baidoo, Kwamena E et al. (2008) Synthesis and biological evaluation of a novel decadentate ligand DEPA. Bioorg Med Chem Lett 18:5792-5
Chong, Hyun-Soon; Song, Hyun A; Ma, Xiang et al. (2008) Novel bimodal bifunctional ligands for radioimmunotherapy and targeted MRI. Bioconjug Chem 19:1439-47
Chong, Hyun-Soon; Ma, Xiang; Le, Thien et al. (2008) Rational design and generation of a bimodal bifunctional ligand for antibody-targeted radiation cancer therapy. J Med Chem 51:118-25
Chong, Hyun-Soon; Mhaske, Santosh; Lin, Mai et al. (2007) Novel synthetic ligands for targeted PET imaging and radiotherapy of copper. Bioorg Med Chem Lett 17:6107-10