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Metal-Free Cycloaddition Chemistry Driven Pretargeted Radioimmunotherapy Using α-Particle Radiation.

  • Shah, Manankumar A1, 2
  • Zhang, Xiuli1, 2
  • Rossin, Raffaella3
  • Robillard, Marc S3
  • Fisher, Darrell R4
  • Bueltmann, Tyler1
  • Hoeben, Freek J M5
  • Quinn, Thomas P1, 2
  • 1 Department of Biochemistry, University of Missouri , Columbia, Missouri 65211, United States. , (United States)
  • 2 Harry S. Truman Veterans Administration Hospital , Columbia, Missouri 65201, United States. , (United States)
  • 3 Tagworks Pharmaceuticals , Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands. , (Netherlands)
  • 4 Versant Medical Physics and Radiation Safety , Richland, Washington 99354, United States. , (United States)
  • 5 SyMO-Chem , Het Kranenveld 14, 5612 AZ Eindhoven, The Netherlands. , (Netherlands)
Published Article
Bioconjugate Chemistry
American Chemical Society
Publication Date
Dec 20, 2017
DOI: 10.1021/acs.bioconjchem.7b00612
PMID: 29129050


The pretargeted radioimmunotherapy approach (PRIT) decouples the administration of tumor targeting monoclonal antibodies (mAbs) from that of the radiolabeled ligand. This multistep strategy allows delivery of high doses of radiation to tumor cells while minimizing nonspecific normal tissue irradiation. In this study, we evaluated the potential of pretargeted α-particle radioimmunotherapy based on the inverse electron demand Diels-Alder (IEDDA) reaction between trans-cyclooctene (TCO) and tetrazine (Tz). Two tetrazine based chelators, DOTA-Tz and TCMC-Tz, were synthesized and compared for their radiolabeling efficiency with 212Pb, radiochemical stability, and in vivo pharmacokinetics. Dosimetry was determined from pretargeted biodistribution studies. The PRIT study was carried out in LS174T tumor bearing mice pretargeted with CC49-TCO mAb. After removing unbound mAbs from the blood using two doses of clearing agent, mice were treated with various doses of (0, 2.78, 4.63, 7.40, and 2 × 2.78 MBq) of 212Pb-DOTA-Tz. 212Pb-DOTA-Tz displayed better in vivo biodistribution than 212Pb-TCMC-Tz and was selected for PRIT study. All the mouse groups receiving treatment displayed a dose dependent reduction in tumor size, while the control groups showed exponential tumor growth. Treatment with 2.78, 4.63, and 2 × 2.78 MBq of 212Pb-DOTA-Tz resulted in statistically significant improvement in median survival (26, 35, and 39 days, respectively). Groups receiving 7.40 MBq of 212Pb-DOTA-Tz and 0.55 MBq of direct labeled CC49 exhibited acute radiation associated toxicity. This study successfully demonstrated that pretargeted 212Pb α-particle therapy resulted in reduced tumor growth rates and improved survival with minimal normal tissue toxicity.

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