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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112503-05
Application #
8607138
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Capala, Jacek
Project Start
2004-12-01
Project End
2017-08-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$284,218
Indirect Cost
$56,794
Name
Illinois Institute of Technology
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
042084434
City
Chicago
State
IL
Country
United States
Zip Code
60616
Kang, Chi Soo; Wu, Ningjie; Chen, Yunwei et al. (2016) Transferrin conjugates of triazacyclononane-based bifunctional NE3TA chelates for PET imaging: Synthesis, Cu-64 radiolabeling, and in vitro and in vivo evaluation. J Inorg Biochem 154:60-6
Kang, Chi Soo; Ren, Siyuan; Sun, Xiang et al. (2016) Theranostic Polyaminocarboxylate-Cyanine-Transferrin Conjugate for Anticancer Therapy and Near-Infrared Optical Imaging. ChemMedChem 11:2188-2193
Wu, Ningjie; Kang, Chi Soo; Sin, Inseok et al. (2016) Promising bifunctional chelators for copper 64-PET imaging: practical (64)Cu radiolabeling and high in vitro and in vivo complex stability. J Biol Inorg Chem 21:177-84
Chong, Hyun-Soon; Chen, Yunwei; Kang, Chi Soo et al. (2015) Novel (64)Cu-radiolabeled bile acid conjugates for targeted PET imaging. Bioorg Med Chem Lett 25:1082-5
Sun, Xiang; Chen, Yunwei; Wu, Ningjie et al. (2015) Application of aziridinium ring opening for preparation of optically active diamine and triamine analogues: Highly efficient synthesis and evaluation of DTPA-based MRI contrast enhancement agents. RSC Adv 5:94571-94581
Kang, Chi Soo; Chen, Yunwei; Lee, Hyunbeom et al. (2015) Synthesis and evaluation of a new bifunctional NETA chelate for molecular targeted radiotherapy using(90)Y or(177)Lu. Nucl Med Biol 42:242-9
Chong, Hyun-Soon; Sun, Xiang; Chen, Yunwei et al. (2015) Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of (90)Y and (177)Lu. Bioorg Med Chem 23:1169-78
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
Kang, Chi Soo; Sun, Xiang; Jia, Fang et al. (2012) Synthesis and preclinical evaluation of bifunctional ligands for improved chelation chemistry of 90Y and 177Lu for targeted radioimmunotherapy. Bioconjug Chem 23:1775-82
Chong, Hyun-Soon; Sun, Xiang; Dong, Pengfei et al. (2011) Convenient Synthesis and Evaluation of Heptadentate Bifunctional Ligand for Radioimmunotherapy Applications. European J Org Chem 2011:6641-6648

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