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Article

Radiolanthanide-Labeled Monoclonal Antibody CC49 for Radioimmunotherapy of Cancer: Biological Comparison of DOTA Conjugates and ¹⁴⁹Pm, ¹⁶⁶Ho, and ¹⁷⁷Lu

Supporting Info

Huma Mohsin,^† Fang Jia,^‡ Geethapriya Sivaguru,^‡ Michael J. Hudson,^§ Tiffani D. Shelton, Timothy J. Hoffman, Cathy S. Cutler, Alan R. Ketring, Phillip S. Athey, Jaime Simón, R. Keith Frank, Silvia S. Jurisson,^†^# and Michael R. Lewis*^‡^#

Department of Chemistry, and Department of Veterinary Medicine and Surgery, University of MissouriColumbia, Columbia, Missouri 65211, Department of Biology, University of Maryland Baltimore County, Baltimore, Maryland 21250, Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri 65201, University of Missouri Research Reactor, University of MissouriColumbia, Columbia, Missouri 65211, Dowpharma, The Dow Chemical Company, Freeport, Texas 77541, and Nuclear Science and Engineering Institute, and Department of Radiology, University of MissouriColumbia, Columbia, Missouri 65211

Bioconjugate Chem., 2006, 17 (2), pp 485–492

DOI: 10.1021/bc0502356

Publication Date (Web): February 23, 2006

†

Department of Chemistry, University of MissouriColumbia.

‡

Department of Veterinary Medicine and Surgery, University of MissouriColumbia.

University of Maryland Baltimore County.

Harry S. Truman Memorial Veterans' Hospital.

University of Missouri Research Reactor, University of MissouriColumbia.

The Dow Chemical Company.

Nuclear Science and Engineering Institute, University of MissouriColumbia.

To whom correspondence should be addressed: Michael R. Lewis, Ph.D., Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, 379 E. Campus Dr., University of MissouriColumbia, Columbia, MO 65211. Phone: (573) 814-6000, ext. 3703. Fax: (573) 814-6551. E-mail: LewisMic@missouri.edu.

Abstract

The radiolanthanides ¹⁴⁹Pm, ¹⁶⁶Ho, and ¹⁷⁷Lu have decay characteristics suitable for radioimmunotherapy (RIT) of cancer. N-Hydroxysulfosuccinimidyl DOTA (DOTA-OSSu) and methoxy-DOTA (MeO-DOTA) were conjugated to the anti-TAG-72 monoclonal antibody CC49 for radiolabeling with ¹⁴⁹Pm, ¹⁶⁶Ho, and ¹⁷⁷Lu. While both DOTA conjugates could be labeled to high specific activity with ¹⁷⁷Lu, MeO-DOTA afforded superior conjugate stability, radiolabeling, and radiochemical purity. Pilot biodistributions in nude mice bearing LS174T human colon carcinoma xenografts demonstrated that MeO-DOTA afforded higher tumor uptake and lower kidney retention of ¹⁷⁷Lu than DOTA-OSSu. The in vitro stability of ¹⁴⁹Pm-, ¹⁶⁶Ho-, and ¹⁷⁷Lu-MeO-DOTA−CC49 was evaluated using serum and hydroxyapatite assays. Serum stability of radiolanthanide-labeled MeO-DOTA−CC49 followed a trend based on the coordination energies of the radiometals, with ¹⁷⁷Lu showing the highest stability after 96 to 168 h at 37 °C. In contrast, MeO-DOTA−CC49 labeled with all three radiolanthanides was >92% stable to hydroxyapatite challenge for 168 h at 37 °C. Comprehensive biodistributions of ¹⁴⁹Pm-, ¹⁶⁶Ho-, and ¹⁷⁷Lu-MeO-DOTA−CC49 were obtained in LS174T-bearing nude mice. Maximum tumor uptakes were 100.0% ID/g for ¹⁴⁹Pm at 96 h, 69.5% ID/g for ¹⁶⁶Ho at 96 h, and 132.4% ID/g for ¹⁷⁷Lu at 168 h. Normal organ uptakes were generally low, except in the liver, spleen, and kidney at early time points. By 96 to 168 h postinjection, nontarget organ uptake decreased to approximately 7% ID/g (kidney), 12% ID/g (spleen), and 20% ID/g (liver) for each radiolanthanide. When labeled with ¹⁴⁹Pm, ¹⁶⁶Ho, and ¹⁷⁷Lu, MeO-DOTA−CC49 has potential for RIT of colorectal cancer and other carcinomas.