Therapeutic efficacy of α-radioimmunotherapy with different activity levels of the 213Bi-labeled monoclonal antibody MX35 in an ovarian cancer model

Springer Science and Business Media LLC - Tập 7 - Trang 1-8 - 2017
Anna Gustafsson-Lutz1, Tom Bäck1, Emma Aneheim1, Ragnar Hultborn2, Stig Palm1, Lars Jacobsson1, Alfred Morgenstern3, Frank Bruchertseifer3, Per Albertsson2, Sture Lindegren1
1Department of Radiation Physics, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
2Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
3European Commission, Joint Research Centre, Institute for Transuranium Elements, Eggenstein-Leopoldshafen, Germany

Tóm tắt

The aim of this study was to compare the therapeutic efficacy of two different activity levels of the 213Bi-labeled monoclonal antibody MX35 in an ovarian cancer model. Sixty female BALB/c (nu/nu) mice were inoculated intraperitoneally with human ovarian cancer cells (OVCAR-3). Two weeks later, 40 mice were injected intraperitoneal (i.p.) with 1 ml of 213Bi-MX35, 3 MBq/mL (n = 20), or 9 MBq/mL (n = 20). An additional 20 mice received unlabeled MX35. Incidence of tumors and ascites was investigated 8 weeks after therapy. Body weight and white blood cell counts were monitored after treatment for possible signs of toxicity. The tumor-free fraction of the animals treated with 3 MBq/mL of 213Bi-MX35 was 0.55, whereas that of animals treated with 9 MBq/mL of 213Bi-MX35 was 0.78. The control group treated with unlabeled MX35 had a tumor-free fraction of 0.15. No significant reduction in white blood cell counts or weight loss was observed. Tumor growth after i.p. treatment with 213Bi-MX35 was significantly reduced compared to treatment with unlabeled MX35. Treatment with 9 MBq/mL of 213Bi-MX35 resulted in higher tumor-free fraction compared with 3 MBq/mL of 213Bi-MX35, but this difference was not statistically significant. No signs of toxicity were observed in the treated animals.

Tài liệu tham khảo

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108. doi:10.3322/caac.21262. Elgqvist J, Andersson H, Back T, Claesson I, Hultborn R, Jensen H, et al. Alpha-radioimmunotherapy of intraperitoneally growing OVCAR-3 tumors of variable dimensions: outcome related to measured tumor size and mean absorbed dose. Journal of Nuclear Medicine. 2006;47:1342–50. Elgqvist J, Andersson H, Back T, Claesson I, Hultborn R, Jensen H, et al. Fractionated radio immunotherapy of intraperitoneally growing ovarian cancer in nude mice with At-211-MX35 F(ab ’)(2): therapeutic efficacy and myelotoxicity. Nucl Med Biol. 2006;33:1065–72. doi:10.1016/j.nucmedbio.2006.07.009. Elgqvist J, Andersson H, Back T, Hultborn R, Jensen H, Karlsson B, et al. Therapeutic efficacy and tumor dose estimations in radioimmunotherapy of intraperitoneally growing OVCAR-3 cells in nude mice with (211)At-labeled monoclonal antibody MX35. J Nucl Med. 2005;46:1907–15. Elgqvist J, Andersson H, Bernhardt P, Back T, Claesson I, Hultborn R, et al. Administered activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with 211At-MX35 F(ab’)2. Int J Radiat Oncol Biol Phys. 2006;66:1228–37. doi:10.1016/j.ijrobp.2006.07.003. Elgqvist J, Andersson H, Jensen H, Kahu H, Lindegren S, Warnhammar E, et al. Repeated intraperitoneal alpha-radioimmunotherapy of ovarian cancer in mice. J Oncol. 2010;2010:394913. doi:10.1155/2010/394913. Palm S, Back T, Claesson I, Danielsson A, Elgqvist J, Frost S, et al. Therapeutic efficacy of astatine-211-labeled trastuzumab on radioresistant SKOV-3 tumors in nude mice. Int J Radiat Oncol Biol Phys. 2007;69:572–9. doi:10.1016/j.ijrobp.2007.06.023. Andersson H, Lindegren S, Back T, Jacobsson L, Leser G, Horvath G. Radioimmunotherapy of nude mice with intraperitoneally growing ovarian cancer xenograft utilizing 211At-labelled monoclonal antibody MOv18. Anticancer Res. 2000;20:459–62. Andersson H, Palm S, Lindegren S, Back T, Jacobsson L, Leser G, et al. Comparison of the therapeutic efficacy of 211At- and 131I-labelled monoclonal antibody MOv18 in nude mice with intraperitoneal growth of human ovarian cancer. Anticancer Res. 2001;21:409–12. Andersson H, Cederkrantz E, Back T, Divgi C, Elgqvist J, Himmelman J, et al. Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)At-MX35 F(ab’)2—a phase I study. J Nucl Med. 2009;50:1153–60. doi:10.2967/jnumed.109.062604. Cederkrantz E, Andersson H, Bernhardt P, Back T, Hultborn R, Jacobsson L, et al. Absorbed doses and risk estimates of (211)At-MX35 F(ab′)2 in intraperitoneal therapy of ovarian cancer patients. Int J Radiat Oncol Biol Phys. 2015;93:569–76. doi:10.1016/j.ijrobp.2015.07.005. Palm S, Back T, Haraldsson B, Jacobsson L, Lindegren S, Albertsson P. Biokinetic modeling and dosimetry for optimizing intraperitoneal radioimmunotherapy of ovarian cancer microtumors. J Nucl Med. 2016;57:594–600. doi:10.2967/jnumed.115.167825. Gustafsson AM, Back T, Elgqvist J, Jacobsson L, Hultborn R, Albertsson P, et al. Comparison of therapeutic efficacy and biodistribution of 213Bi- and 211At-labeled monoclonal antibody MX35 in an ovarian cancer model. Nucl Med Biol. 2012;39:15–22. doi:10.1016/j.nucmedbio.2011.07.003. Apostolidis C, Molinet R, Rasmussen G, Morgenstern A. Production of Ac-225 from Th-229 for targeted alpha therapy. Anal Chem. 2005;77:6288–91. doi:10.1021/ac0580114. Zielinska B, Apostolidis C, Bruchertseifer F, Morgenstern A. An improved method for the production of Ac-225/Bi-213 from Th-229 for targeted alpha therapy. Solvent Extr Ion Exc. 2007;25:339–49. doi:10.1080/07366290701285108. Nikula TK, McDevitt MR, Finn RD, Wu C, Kozak RW, Garmestani K, et al. Alpha-emitting bismuth cyclohexylbenzyl DTPA constructs of recombinant humanized anti-CD33 antibodies: pharmacokinetics, bioactivity, toxicity and chemistry. J Nucl Med. 1999;40:166–76. Mattes MJ, Lloyd KO, Lewis JL. Binding parameters of monoclonal antibodies reacting with ovarian carcinoma ascites cells. Cancer Immunol Immun. 1989;28:199–207. Mattes MJ, Look K, Furukawa K, Pierce VK, Old LJ, Lewis JL, et al. Mouse monoclonal antibodies to human epithelial differentiation antigens expressed on the surface of ovarian carcinoma ascites cells. Cancer Res. 1987;47:6741–50. Yin BW, Kiyamova R, Chua R, Caballero OL, Gout I, Gryshkova V, et al. Monoclonal antibody MX35 detects the membrane transporter NaPi2b (SLC34A2) in human carcinomas. Cancer Immun. 2008;8:3. Pippin CG, Parker TA, McMurry TJ, Brechbiel MW. Spectrophotometric method for the determination of a bifunctional DTPA ligand in DTPA-monoclonal antibody conjugates. Bioconjug Chem. 1992;3:342–5. Lindmo T, Boven E, Cuttitta F, Fedorko J, Bunn PA. Determination of the immunoreactive fraction of radiolabeled monoclonal-antibodies by linear extrapolation to binding at infinite antigen excess. J Immunol Methods. 1984;72:77–89. doi:10.1016/0022-1759(84)90435-6. Elgqvist J, Bernhardt P, Hultborn R, Jensen H, Karlsson B, Lindegren S, et al. Myelotoxicity and RBE of 211At-conjugated monoclonal antibodies compared with 99mTc-conjugated monoclonal antibodies and 60Co irradiation in nude mice. J Nucl Med. 2005;46:464–71. Back T, Haraldsson B, Hultborn R, Jensen H, Johansson ME, Lindegren S, et al. Glomerular filtration rate after alpha-radioimmunotherapy with At-211-MX35-F(ab ’)(2): a long-term study of renal function in nude mice. Cancer Biother Radio. 2009;24:649–58. doi:10.1089/cbr.2009.0628. Back T, Elgqvist J, Hultborn R, Kahu H, Lindegren S, Palm S, et al. Irradiation effects on the kidneys after radioinimunotherapy with the alpha emitter astatine-211: report from an on-going long-term study in nude mice. Cancer Biother Radio. 2006;21:396–7. Cederkrantz E, Angenete E, Back T, Falk P, Haraldsson B, Ivarsson ML, et al. Evaluation of effects on the peritoneum after intraperitoneal alpha-radioimmunotherapy with (211)At. Cancer Biother Radiopharm. 2012;27:353–64. doi:10.1089/cbr.2012.1184.