Megan Minnix1,2, Lin Li1, Paul J Yazaki1, Aaron D Miller1, Junie Chea3, Erasmus Poku3, An Liu4, Jeffrey Y C Wong4, Russell C Rockne5, David Colcher1, John E Shively6. 1. Department of Molecular Imaging and Therapy, Beckman Research Institute, City of Hope, Duarte, California. 2. Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, California. 3. Radiopharmacy, City of Hope Medical Center, Duarte, California. 4. Department of Radiation Oncology, City of Hope Medical Center, Duarte, California; and. 5. Division of Mathematical Oncology, Beckman Research Institute, City of Hope, Duarte, California. 6. Department of Molecular Imaging and Therapy, Beckman Research Institute, City of Hope, Duarte, California jshively@coh.org.
Abstract
Radioimmunotherapy, an approach using radiolabeled antibodies, has had minimal success in the clinic with several β-emitting radionuclides for the treatment of ovarian cancer. Alternatively, radioimmunotherapy with α-emitters offers the advantage of depositing much higher energy over shorter distances but was thought to be inappropriate for the treatment of solid tumors, for which antibody penetration is limited to a few cell diameters around the vascular system. However, the deposition of high-energy α-emitters to tumor markers adjacent to a typical leaky tumor vascular system may have large antitumor effects at the tumor vascular level, and their reduced penetration in normal tissue would be expected to lower off-target toxicity. Methods: To evaluate this concept, DOTAylated-huCC49 was labeled with the α-emitter 225Ac to target tumor-associated glycoprotein 72-positive xenografts in a murine model of ovarian cancer. Results: 225Ac-labeled DOTAylated-huCC49 radioimmunotherapy significantly reduced tumor growth in a dose-dependent manner (1.85, 3.7, and 7.4 kBq), with the 7.4-kBq dose extending survival by more than 3-fold compared with the untreated control. Additionally, a multitreatment regime (1.85 kBq followed by 5 weekly doses of 0.70 kBq for a total of 5.4 kBq) extended survival almost 3-fold compared with the untreated control group, without significant off-target toxicity. Conclusion: These results establish the potential for antibody-targeted α-radionuclide therapy for ovarian cancer, which may be generalized to α-radioimmunotherapy in other solid tumors.
Radioimmunotherapy, an approach using radiolabeled antibodies, has had minimal success in the clinic with several β-emitting radionuclides for the treatment of ovarian cancer. Alternatively, radioimmunotherapy with α-emitters offers the advantage of depositing much higher energy over shorter distances but was thought to be inappropriate for the treatment of solid tumors, for which antibody penetration is limited to a few cell diameters around the vascular system. However, the deposition of high-energy α-emitters to tumor markers adjacent to a typical leaky tumor vascular system may have large antitumor effects at the tumor vascular level, and their reduced penetration in normal tissue would be expected to lower off-target toxicity. Methods: To evaluate this concept, DOTAylated-huCC49 was labeled with the α-emitter 225Ac to target tumor-associated glycoprotein 72-positive xenografts in a murine model of ovarian cancer. Results: 225Ac-labeled DOTAylated-huCC49 radioimmunotherapy significantly reduced tumor growth in a dose-dependent manner (1.85, 3.7, and 7.4 kBq), with the 7.4-kBq dose extending survival by more than 3-fold compared with the untreated control. Additionally, a multitreatment regime (1.85 kBq followed by 5 weekly doses of 0.70 kBq for a total of 5.4 kBq) extended survival almost 3-fold compared with the untreated control group, without significant off-target toxicity. Conclusion: These results establish the potential for antibody-targeted α-radionuclide therapy for ovarian cancer, which may be generalized to α-radioimmunotherapy in other solid tumors.
Authors: Emilio Bombardieri; Francesco Giammarile; Cumali Aktolun; Richard P Baum; Angelika Bischof Delaloye; Lorenzo Maffioli; Roy Moncayo; Luc Mortelmans; Giovanna Pepe; Sven N Reske; Maria R Castellani; Arturo Chiti Journal: Eur J Nucl Med Mol Imaging Date: 2010-12 Impact factor: 9.236
Authors: Lin Li; James Bading; Paul J Yazaki; Amitkumar H Ahuja; Desiree Crow; David Colcher; Lawrence E Williams; Jeffrey Y C Wong; Andrew Raubitschek; John E Shively Journal: Bioconjug Chem Date: 2007-11-08 Impact factor: 4.774
Authors: Johnnie J Orozco; Tom Bäck; Aimee Kenoyer; Ethan R Balkin; Donald K Hamlin; D Scott Wilbur; Darrell R Fisher; Shani L Frayo; Mark D Hylarides; Damian J Green; Ajay K Gopal; Oliver W Press; John M Pagel Journal: Blood Date: 2013-03-07 Impact factor: 22.113
Authors: Paul E Borchardt; Rui R Yuan; Matthias Miederer; Michael R McDevitt; David A Scheinberg Journal: Cancer Res Date: 2003-08-15 Impact factor: 12.701
Authors: Robin I J Merkx; Mark Rijpkema; Gerben M Franssen; Annemarie Kip; Bart Smeets; Alfred Morgenstern; Frank Bruchertseifer; Eddie Yan; Michael P Wheatcroft; Egbert Oosterwijk; Peter F A Mulders; Sandra Heskamp Journal: Pharmaceuticals (Basel) Date: 2022-05-02