Review

Application of 212Pb for Targeted α-particle Therapy (TAT): Pre-clinical and Mechanistic Understanding through to Clinical Translation

  • Received: 20 April 2015 Accepted: 12 August 2015 Published: 18 August 2015
  • Targeted α-particle therapy (TAT), in which an α-particle emitting radionuclide is specifically directed to a biological target, is gaining more attention to treat cancers as new targets are validated. Bio-vectors such as monoclonal antibodies are able to selectively transport α-particles to destroy targeted cancer cells. TAT has the potential for an improved therapeutic ratio over β-particle targeted conjugate therapy. The short path length and the intense ionization path generated render α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking. 212Pb is the longer-lived parent radionuclide of 212Bi and serves as an in vivo generator of 212Bi. 212Pb has demonstrated significant utility in both in vitro and in vivo models. Recent evaluation of 212Pb-TCMC-trastuzumab in a Phase I clinical trial has demonstrated the feasibility of 212Pb in TAT for the treatment of ovarian cancer patients. This review highlights progress in radionuclide production, radiolabeling chemistry, molecular mechanisms, and application of 212Pb to targeted pre-clinical and clinical radiation therapy for the management and treatment of cancer.

    Citation: Kwon Yong, Martin Brechbiel. Application of 212Pb for Targeted α-particle Therapy (TAT): Pre-clinical and Mechanistic Understanding through to Clinical Translation[J]. AIMS Medical Science, 2015, 2(3): 228-245. doi: 10.3934/medsci.2015.3.228

    Related Papers:

  • Targeted α-particle therapy (TAT), in which an α-particle emitting radionuclide is specifically directed to a biological target, is gaining more attention to treat cancers as new targets are validated. Bio-vectors such as monoclonal antibodies are able to selectively transport α-particles to destroy targeted cancer cells. TAT has the potential for an improved therapeutic ratio over β-particle targeted conjugate therapy. The short path length and the intense ionization path generated render α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking. 212Pb is the longer-lived parent radionuclide of 212Bi and serves as an in vivo generator of 212Bi. 212Pb has demonstrated significant utility in both in vitro and in vivo models. Recent evaluation of 212Pb-TCMC-trastuzumab in a Phase I clinical trial has demonstrated the feasibility of 212Pb in TAT for the treatment of ovarian cancer patients. This review highlights progress in radionuclide production, radiolabeling chemistry, molecular mechanisms, and application of 212Pb to targeted pre-clinical and clinical radiation therapy for the management and treatment of cancer.



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    [1] Zalutsky MR, Bigner DD (1996) Radioimmunotherapy with α-particle emitting radioummunoconjugates. Acta Oncol 35:373-379. doi: 10.3109/02841869609101654
    [2] Milenic DE, Brady ED, Brechbiel MW (2004) Antibody targeted radiation cancer therapy. Nat Rev Drug Discov 3:488-499. doi: 10.1038/nrd1413
    [3] Allen BJ, Raja C, Rizvi S, et al. (2004) Targeted alpha therapy for cancer. Phys Med Biol 49:3703-3712. doi: 10.1088/0031-9155/49/16/016
    [4] Brechbiel MW (2007) Targeted α-therapy:past, present, future? Dalton Trans 43:4918-4928.
    [5] Kiston SL, Cuccurullo V, Moody TS, et al. (2013) Radionuclide antibody-conjugates, α- targeted therapy towards cancer. Curr Radiopharm 6:57-71. doi: 10.2174/1874471011306020001
    [6] McDevitt MR, Sgouros G, Finn RD, et al. (1998) Radioimmunotherapy with alpha-emitting nuclides. Eur J Nucl Med 25:1341-1351. doi: 10.1007/s002590050306
    [7] Ramogida CF, Orvig C (2013) Tumour targeting with radiometals for diagnosis and therapy. Chem Comm 49:4720-4739. doi: 10.1039/c3cc41554f
    [8] Elgqvist J, Andersson H, Back T, et al. (2005) Therapeutic efficacy and tumor dose estimations in radioimmunotherapy of intraperitoneally growing OVCR-3 cells in nude mice with 211At-labeled monoclonal antibody MX35. J Nucl Med 46:1907-1915.
    [9] Milenic D, Gamestani K, Dadachova E, et al. (2004) Radioimmunotherapy of human colon carcinoma xenografts using a 213Bi labeled domain deleted humanized monoclonal antibody. Cancer Biother Radiopharm 19:135-147. doi: 10.1089/108497804323071904
    [10] Milenic DE, Garmestani K, Brady ED, et al. (2005) Alpha-particle radioimmunitherapy of disseminated peritoneal diseases using a 212Pb-labeled radioimmunoconjugate targeting HER2. Cancer Biother Radiopharm 20:557-568. doi: 10.1089/cbr.2005.20.557
    [11] Yong KJ, Milenic DE, Baidoo KE, et al. (2012) 212Pb-radioimmunotherapy induces G2 cell-cycle arrest and delays DNA damage repair in tumor xenografts in a model for disseminated intraperitoneal disease. Mol Cancer Ther 11:639-648. doi: 10.1158/1535-7163.MCT-11-0671
    [12] Yong KJ, Milenic DE, Baidoo KE, et al. (2013) Gene expression profiling upon 212Pb-TCMC-trastuzumab treatment in the LS-174T i.p. xenograft model. Cancer Med 2:646-653.
    [13] Meredith RF, Torgue J, Azure MT, et al. (2014) Pharmacokinetics and imaging of 212Pb-TCMC-trastuzumab after intraperitoneal administration in ovarian cancer patients. Cancer Biother Radiopharm 29:12-17. doi: 10.1089/cbr.2013.1531
    [14] Kim YS, Brechbiel MW (2012) An overview of targeted alpha therapy. Tumor Biol 33:573-590. doi: 10.1007/s13277-011-0286-y
    [15] Atcher R.W, Friedman AM, Hines JJ (1988) An improved generator for the production of 212Pb and 212Bi from 224Ra. Int J Rad Appl Instrum A 39:283-286. doi: 10.1016/0883-2889(88)90016-0
    [16] Atcher RW, Hines JJ, Friedman AM (1987) A remote system for the separation of 228Th and 224Ra. J Radioanal Nucl Chem 117:155-162. doi: 10.1007/BF02165369
    [17] Baidoo KE, Milenic DE, Brechbiel MW (2013) Methodology for labeling proteins and peptides with lead-212(212Pb). Nucl Med Biol 40:592-599. doi: 10.1016/j.nucmedbio.2013.01.010
    [18] Mirzadeh S, Brechbiel MW, Atcher RW, et al. (1990) Radiometal labeling of immunoproteins: covalent linkage of 2-(4-isothiocyanatobenzyl)diethylenetriaminepentaacetic acid ligands to immunoglobulin. Bioconjug Chem 1:59-65. doi: 10.1021/bc00001a007
    [19] Howell RW, Axure MT, Narra VR, et al. (1994) Relative biological effectiveness of alpha particle emitters in vivo at low doses. Radiat Res 137:352-360. doi: 10.2307/3578710
    [20] www.NIST.gov
    [21] Ruegg CL, Anderson-Berg ET, Brechbiel MW, et al. (1990) Improved in vivo stability and tumor targeting of bismuth-labeled antibody. Cancer Res 50:4221-4226.
    [22] Chappell LL, Dadachova E, Milenic DE, et al. (2000) Synthesis, characterization, and evaluation of a novel bifunctional chelating agent for the lead isotope 203Pb and 212Pb. Nucl Med Biol 27:93-100. doi: 10.1016/S0969-8051(99)00086-4
    [23] Ruble G, Wu C, Squire RA, et al. (1996) The use of 212Pb-labeled monoclonal antibody in the treatment of murine erythroleukemia. Int J Radiat Oncol Biol Phys 34:609-616. doi: 10.1016/0360-3016(95)02119-1
    [24] McMurry TJ, Brechbiel MW, Kumar K, et al. (1992) Convenient synthesis of bifunctional tetraaza macrocycles. Bioconjugate Chem 3:108-117. doi: 10.1021/bc00014a004
    [25] Cuenot F, Meyer M, Espinosa E, et al. (2008) New insights into the complexation of lead(II) by 1,4,7,10-tetrakis(carbamoylmetyl)-1,4,7,10-tetraazacyclododecane (DOTAM): structural, thermodynamic, and kinetic studies. Eur J Inorg Chem 267-283.
    [26] Clynes RA, Towers TL, Presta LG, et al. (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nature Med 6:443-446. doi: 10.1038/74704
    [27] Johnson P, Glennie M (2003) The mechanisms of action of rituximab in the elimination of tumor cells. Semin Oncol 30:3–8.
    [28] Pegram MD, Lipton A, Hayes DF, et al. (1998) Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185(HER2/neu) monoclonal antibody plus cisplatin in patients with HER2/neu overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 16:2659-2671.
    [29] Menard C, Smith IC, Somorjai RL, et al. (2001) Magnetic resonance of the malignant prostate gland after radiotherapy: a histopathologic study of diagnostic validity. Int J Radiat Oncol Biol Phys 50:317-323. doi: 10.1016/S0360-3016(01)01480-8
    [30] Kim YS, Konoplev SN, Montemurro F, et al. (2001) Her-2/neu overexpression as a poor prognostic factor for patients with metastatic breast cancer undergoing high-dose chemotherapy with autologous stem cell transplantation. Clin Cancer Res 7:4008-4012.
    [31] www.ClinicalTrials.gov
    [32] Macey DJ, Meredith RF (1999) A strategy to reduce red marrow dose for intraperitoneal radioimmunotherapy. Clin Cancer Res 5:3044-3047.
    [33] Milenic DE, Gamestani K, Brady ED, et al. (2007) Potentiation of high-LET radiation by gemcitabine: targeting HER2 with trastuzumab to treat disseminated peritoneal disease. Clin Cancer Res 13:1926-1935. doi: 10.1158/1078-0432.CCR-06-2300
    [34] Milenic DE, Gamestani K, Brady ED, et al. (2008) Multimodality therapy: Potentiation of high linear energy transfer radiation with paclitaxel for the treatment of disseminated peritoneal disease. Clin Cancer Res 14:5108-5115. doi: 10.1158/1078-0432.CCR-08-0256
    [35] Steiner M, Neri D (2011) Antibody-radionuclide conjugates for cancer therapy: historical considerations and new trends. Clin Cancer Res 17:6406-6416. doi: 10.1158/1078-0432.CCR-11-0483
    [36] Olasfen T, Elgqvist J, Wu AM (2011) Protein targeting constructs in alpha therapy. Curr Radiopharm 4:197-213. doi: 10.2174/1874471011104030197
    [37] Su FM, Beaumier P, Axworthy D, et al. (2005) Pre-targeted radioimmunotherapy in tumored mice using an in vivo 212Pb/212Bi generator. Nucl Med Biol 32:741-747. doi: 10.1016/j.nucmedbio.2005.06.009
    [38] Miao Y, Figueroa SD, Fisher DR, et al. (2008) 203Pb-labeled alpha-melanocyte-stimulating hormone peptide as an imaging probe for melanoma detection. J Nucl Med 49:823-829.
    [39] Rosenow MK, Xucchini GL, Bridwell PM, et al. (1983) Properties of liposomes containing 212Pb. Int J Nucl Med Biol 10:189-197. doi: 10.1016/0047-0740(83)90078-5
    [40] Diener MD, Alford JM, Kennel SJ, et al. (2007) 212Pb@C(60) and its water-soluble derivatives: synthesis, stability, and suitability for radioimmunotherapy. J Am Chem Soc 129:5131-5138. doi: 10.1021/ja068639b
    [41] International commission on radiation doses to body tissues from international contamination to occupational exposure. 1st ed. Oxford:Pergamon 1968:94p.
    [42] Loveinger R, Berman M (1968) A formalism for calculation of absorbed dose from radionuclides. Phys Med Biol 13:205-217. doi: 10.1088/0031-9155/13/2/306
    [43] Bolch WE, Eckerman KF, Sgouros G, et al. (2009) MIRD pamphlet no.21: a generalized schema for radiopharmaceutical dosimetry-standardization of nomenclature. J Nucl Med 50:477-484.
    [44] Sgouros G, Roeske JC, McDevitt MR, et al. (2010) MIRD Phamplet No 22: radiobiology and dosimetry of α-particle emitters for targeted radionuclide therapy. J Nucl Med 51:311-328. doi: 10.2967/jnumed.108.058651
    [45] Zanzonico PB (2000) Internal radionuclide radiation dosimetry: a review of basic concepts and recent developments. J Nucl Med 41:297-308.
    [46] Buchsbaum DJ, Langmuir VK, Wessels BW (1993) Experimental radioimmunotherapy. Med Phys 20:551-567. doi: 10.1118/1.597142
    [47] Chouin N, Bardies M (2011) Alpha-particle microdosimetry. Curr Radiopharm 4:266-280. doi: 10.2174/1874471011104030266
    [48] Boudousq V, Busson M, Bobyk L, et al. (2013) Comparison between internalizing anti-HER2 mAbs and non-internalizing anti-CEA mAbs in α-radioimmunotherapy of small volume peritoneal cacinomatosis using 212Pb. PloS One 8:e69613
    [49] Back T, Jacobsson L (2010) The alpha-camera: a quantitative digital autoradiography technique using a charge-coupled device for ex vivo high-resolution bio-imaging of alpha-particles. J Nucl Med 51:1616-1623. doi: 10.2967/jnumed.110.077578
    [50] Okada H, Mak TW (2004) Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 4:592-603. doi: 10.1038/nrc1412
    [51] Sqouros G, Roeske JC, McDevitt MR, et al. (2010) MIRD pamphlet no. 22 (abridged): radiobiology and dosimetry of alpha-particle emitters for targeted radionuclide therapy. J Nucl Med 51:311-328.
    [52] Bruland OS, Nilsson S, Fisher DR, et al. (2006) High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res 126250-6257.
    [53] Dimri GP (2005) What has senescence got to do with cancer? Cancer Cell 7:505-512. doi: 10.1016/j.ccr.2005.05.025
    [54] Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205-219. doi: 10.1016/S0092-8674(04)00046-7
    [55] Lum JJ, DeBerardinis RJ, Thompson CB (2005) Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 6:439-448. doi: 10.1038/nrm1660
    [56] Castedo M, Perfettini JL, Roumier T, et al. (2004) Cell death by mitotic catastrophe: a molecular definition. Oncogene 23:2825-2837. 57. Chouin N, Lindegren S, Frost SH, et al. (2013) Ex vivo activity quantification in micrometastases at the cellular scale using the α-camera technique. J Nucl Med 54:1347-1353. doi: 10.2967/jnumed.112.113001
    [57] 58. Pouget JP, Mather SJ (2001) General aspects of the cellular response to low- and high-LET radiation. Eur J Nucl Med 28:541-561. doi: 10.1007/s002590100484
    [58] 59. Tompson LH (2012) Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography. Mutation Res 751:1 united doi: 10.1016/j.mrrev.2012.06.002
    [59] 60. Teshima T, Owen JB, Hanks GE, et al. (1996) A Comparison of the structure of radiation oncology in the United States and Japan. Int J Radiat Oncol Biol Phys 34:243-250. doi: 10.1016/0360-3016(95)02049-7
    [60] 61. Physician Characteristics and Distribution in the US, 2008 Edition. (https://www.astro.org/News-and-Media/Media-Resources/FAQs/Fast-Facts-About-Radiation-Therapy/Index.aspx)
    [61] 62. Friesen C, Glatting G, Koop B, et al. (2007) Breaking chemoresistance and radioresistance with 213Bi anti-CD45 antibodies in leukemia cells. Cancer Res 67:1950-1958. doi: 10.1158/0008-5472.CAN-06-3569
    [62] 63. Supiot S, Gouard S, Charrier J, et al. (2005) Mechanisms of cell sensitization to α-radioimmunotherapy by doxorubicin or paclitaxel in multiple myeloma cell lines. Clin Cancer Res 11:7047-7052. doi: 10.1158/1078-0432.CCR-1004-0021
    [63] 64. Tochi L, Finocchiaro G, Bartolini S, et al. (2005) Role of gemcitabine in cancer therapy. Future Oncol 1:7-17. doi: 10.1517/14796694.1.1.7
    [64] 65. Yong KJ, Milenic DE, Baidoo KE, et al. (2013) Sensitization of tumor to 212Pb radioimmunotherapy by gemcitabine involves initial abrogation of G2 arrest and blocked DNA damage repair by interfere with Rad51. Int J Radiat Oncol Biol Phys 85:1119-1126. doi: 10.1016/j.ijrobp.2012.09.015
    [65] 66. Yong KJ, Milenic DE, Baidoo KE, et al. (2013) 212Pb-radioimmunotherapy potentiates paclitaxel-induced cell killing efficacy by perturbing the mitotic spindle checkpoint. Br J Cancer 108:2013-2020. doi: 10.1038/bjc.2013.189
    [66] 67. Yong KJ, Milenic DE, Baidoo KE, et al. (2014) Impact of α-targeted radiation therapy on gene expression in a pre-clinical model for disseminated peritoneal disease when combined with paclitaxel. PloS One 9:e108511. doi: 10.1371/journal.pone.0108511
    [67] 68. Milenic DE, Baidoo KE, Shin JH, et al. (2013) Evaluation of platinum chemotherapy in combination with HER2-targeted a-particle radiation. Cancer Biother Radiopharm 28:441-449. doi: 10.1089/cbr.2012.1423
    [68] 69. Tan Z, Chen P, Schneider N, et al. (2012) Significant systemic therapeutic effects of high-LET immunoradiation by 212Pb-trastuzumab against tumors of androgen-independent human prostate cancer in mice. Int J Oncol 40:1881.
    [69] 70. Andersson H, Elgqvist J, Horvath G, et al. (2003) Astatine-211-labeled antibodies for treatment of disseminated ovarian cancer: an overview of results in an ovarian tumor model. Clin Cancer Res 9:S3914-3921.
    [70] 71. Ward BG, Mather SJ, Hawkins LR, et al. (1987) Localization of radioiodine conjugated to the monoclonal antibody HMFG2 in human ovarian carcinoma: assessment of intravenous and intraperitoneal routes of administration. Cancer Res 47:4719-4723.
    [71] 72. Verheijen RH, Massuger LF, Benigno BB, et al. (2006) Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission. J Clin Oncol 24:5578. doi: 10.1200/JCO.2005.02.5973
    [72] 73. Elgqvist J, Andersson H, Bernhardt P, et al. (2006) Adiministrated activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with 211At-MX35F(ab’)2. Int J Radiat Oncol Biol Phys 66:1228-1237. doi: 10.1016/j.ijrobp.2006.07.003
    [73] 74. Andersson H, Cederkranz E, Back T, et al. (2009) Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)At-MX35F(ab’)2- a phase I study. J Nucl Med 50:1153-1160. doi: 10.2967/jnumed.109.062604
    [74] 75. Meredith R, Torgue J, Shen S, et al. (2014) Dose escalation and dosimetry of first-in-human α-radioimmunotherapy with 212Pb-TCMC-trastuzumab. J Nucl Med 551636-551642.
    [75] 76. Milenic DE, Baidoo KE, Kim YS, et al. (2015) Evaluation of cetuximab as a candidate for targeted a-particle radiation therapy of HER1-positive disseminated intraperitoneal disease. Mabs 7:255-264. doi: 10.4161/19420862.2014.985160
    [76] 77. Wong KJ, Baidoo KE, Nayak TK, et al. (2011) In vitro and in vivo pre-clinical analysis of a F(ab’)2 fragment of panitumumab for molecular imaging and therapy of HER1 positive cancers. EJNMMI Res 1:doi:10.1186/2191-219x-1-1.
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