1 Malaise, E. P., Fertil, B., Chavaudra, N. & Guichard, M. Distribution of radiation sensitivities for human tumor cells of specific histological types: comparison of in vitro to in vivo data. Int. J. Radiat. Oncol. Biol. Phys. 12, 617–624 (1986).

2 Scott, A. M., Wolchok, J. D. & Old, L. J. Antibody therapy of cancer. Nature Reviews Cancer 12, 278–287 (2012). Valuable review of the general concepts of antigen targets on human tumours and the non-radioactive use of antibodies as therapeutics.

3 Kaminski, M. S. et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N. Engl. J. Med. 352, 441–449 (2005). Benefits of up-front treatment by RIT in lymphoma.

4 Press, O. W. et al. Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support. N. Engl. J. Med. 329, 1219–1224 (1993). First demonstration of the ability to achieve long-term remission with radioantibodies using RIT in advanced lymphoma.

5 Witzig, T. E. et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J. Clin. Oncol. 20, 3262–3269 (2002).

6 DeNardo, G. L. et al. Maximum-tolerated dose, toxicity, and efficacy of 131I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin's lymphoma. J. Clin. Oncol. 16, 3246–3256 (1998).

7 Sharkey, R. M. et al. Pretargeted versus directly targeted radioimmunotherapy combined with anti-CD20 antibody consolidation therapy of non-Hodgkin lymphoma. J. Nucl. Med. 50, 444–453 (2009).

8 Morschhauser, F. et al. High rates of durable responses with anti-CD22 fractionated radioimmunotherapy: results of a multicenter, Phase I/II study in non-Hodgkin's lymphoma. J. Clin. Oncol. 28, 3709–3716 (2010).

9 Rosenblat, T. L. et al. Sequential cytarabine and α-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin. Cancer Res. 16, 5303–5311 (2010).

10 Pagel, J. M. et al. Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood 114, 5444–5453 (2009). Benefits of preconditioning with RIT in elderly patients undergoing bone marrow transplantation for advanced acute myleoid leukaemia and high-risk myelodysplastic syndrome.

11 Pagel, J. M. et al. A comparative analysis of conventional and pretargeted radioimmunotherapy of B-cell lymphomas by targeting CD20, CD22, and HLA-DR singly and in combinations. Blood 113, 4903–4913 (2009).

12 Tedder, T. F. & Engel, P. CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol. Today 15, 450–454 (1994).

13 Chang, K. L., Arber, D. A. & Weiss, L. M. CD20: a review. Appl. Immunohistochem. 4, 1–15 (1996).

14 Press, O. W. Radioimmunotherapy for non-Hodgkin's lymphomas: a historical perspective. Semin. Oncol. 30, 10–21 (2003).

15 Press, O. W. & Rasey, J. Principles of radioimmunotherapy for hematologists and oncologists. Semin. Oncol. 27, 62–73 (2000). A general review of the principles of RIT.

16 Press, O. W. Physics for practitioners: the use of radiolabeled monoclonal antibodies in B-cell non-Hodgkin's lymphoma. Seminars Hematol. 37 (Suppl. 7), 2–8 (2000).

17 Naruki, Y. et al. Differential cellular catabolism of 111In, 90Y and 125I radiolabeled T101 anti-CD5 monoclonal antibody. Int. J. Rad Appl. Instrum. B 17, 201–207 (1990). Initial comparison of the differential metabolism of radiometals and radioiodine as radiolabels for RIT.

18 Geissler, F., Anderson, S. K. & Press, O. Intracellular catabolism of radiolabeled anti-CD3 antibodies by leukemic T cells. Blood 78, 1864–1874 (1991).

19 Geissler, F., Anderson, S. K., Venkatesan, P. & Press, O. Intracellular catabolism of radiolabeled anti-μ antibodies by malignant B-cells. Cancer Res. 52, 2907–2915 (1992).

20 Press, O. W. et al. Comparative metabolism and retention of iodine-125, yttrium-90, and indium-111 radioimmunoconjugates by cancer cells. Cancer Res. 56, 2123–2129 (1996).

21 Kaminski, M. S. et al. Pivotal study of iodine I-131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphomas. J. Clin. Oncol. 19, 3918–3928 (2001).

22 Witzig, T. E. et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J. Clin. Oncol. 20, 2453–2463 (2002).

23 Press, O. W. et al. Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas. Lancet 346, 336–340 (1995).

24 Zalutsky, M. R. Targeted α-particle therapy of microscopic disease: providing a further rationale for clinical investigation. J. Nucl. Med. 47, 1238–1240 (2006). Rationale for α-particle therapy illustrated with 211At.

25 Jurcic, J. G. et al. Targeted α particle immunotherapy for myeloid leukemia. Blood 100, 1233–1239 (2002). Early work with 225Ac.

26 Hall, E. J. & Giaccia, A. J. Radiobiology for the Radiologist (Lippincott Williams & Wilkins, 2005).

27 Mulford, D. A., Scheinberg, D. A. & Jurcic, J. G. The promise of targeted α-particle therapy. J. Nucl Med 46 (Suppl. 1), 199S–204S (2005).

28 Zalutsky, M. R. & Pozzi, O. R. Radioimmunotherapy with α-particle emitting radionuclides. Q. J. Nucl. Med. Mol. Imaging 48, 289–296 (2004).

29 Couturier, O. et al. Cancer radioimmunotherapy with α-emitting nuclides. Eur. J. Nucl. Med. Mol. Imaging 32, 601–614 (2005).

30 McDevitt, M. R. et al. Tumor therapy with targeted atomic nanogenerators. Science 294, 1537–1540 (2001). The concept of the α-emitter 225Ac as an in vivo nanogenerator.

31 Nilsson, S. et al. First clinical experience with α-emitting radium-223 in the treatment of skeletal metastases. Clin. Cancer Res. 11, 4451–4459 (2005).

32 Miederer, M. et al. Pharmacokinetics, dosimetry, and toxicity of the targetable atomic generator, 225Ac-HuM195, in nonhuman primates. J. Nucl. Med. 45, 129–137 (2004).

33 Dahle, J. et al. Targeted cancer therapy with a novel low-dose rate α-emitting radioimmunoconjugate. Blood 110, 2049–2056 (2007).

34 Waldmann, T. ABCs of radioisotopes used for radioimmunotherapy: α- and β-emitters. Leuk. Lymphoma 44 (Suppl. 3), S107–S113 (2003).

35 He, P. et al. Two-compartment model of radioimmunotherapy delivered through cerebrospinal fluid. Eur. J. Nucl. Med. Mol. Imaging 38, 334–342 (2011).

36 Kramer, K. et al. Phase I study of targeted radioimmunotherapy for leptomeningeal cancers using intra-Ommaya 131-I-3F8. J. Clin. Oncol. 25, 5465–5470 (2007). Induction of long-term responses in recurrent neuroblastoma with RIT.

37 Kramer, K. et al. Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. J. Neurooncol. 97, 409–418 (2010). Documentation of an active intrathecal RIT regimen in patients with relapsed CNS neuroblastoma.

38 Kramer, K. B. et al. ANR Congress. ANR Congress [online], (2014).

39 Carrasquillo, J. A. et al. (124)I-huA33 antibody PET of colorectal cancer. J. Nucl. Med. 52, 1173–1180 (2011). Presurgical PET study of antibody targeting of CRC liver metastases as an optimal clinical research design for the study of radioantibody targeting in vivo.

40 O'Donoghue, J. A. et al. 124I-huA33 antibody uptake is driven by A33 antigen concentration in tissues from colorectal cancer patients imaged by immuno-PET. J. Nucl. Med. 52, 1878–1885 (2011). Law of mass action drives antibody–antibody binding at the tumour site.

41 Wittrup, K. D., Thurber, G. M., Schmidt, M. M. & Rhoden, J. J. Practical theoretic guidance for the design of tumor-targeting agents. Methods Enzymol. 503, 255–268 (2012). The role of diffusion into the tumour, the internalization of antigen and renal clearance in tumour targeting.

42 Fujimori, K., Covell, D. G., Fletcher, J. E. & Weinstein, J. N. A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier. J. Nucl. Med. 31, 1191–1198 (1990). Initial description of a binding site barrier in RIT.

43 Pagel, J. M. et al. 131I-anti-CD45 antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute myeloid leukemia in first remission. Blood 107, 2184–2191 (2006).

44 Winter, J. N. et al. Yttrium-90 ibritumomab tiuxetan doses calculated to deliver up to 15 Gy to critical organs may be safely combined with high-dose BEAM and autologous transplantation in relapsed or refractory B-cell non-Hodgkin's lymphoma. J. Clin. Oncol. 27, 1653–1659 (2009).

45 Devizzi, L. et al. High-dose yttrium-90-ibritumomab tiuxetan with tandem stem-cell reinfusion: an outpatient preparative regimen for autologous hematopoietic cell transplantation. J. Clin. Oncol. 26, 5175–5182 (2008).

46 Nademanee, A. et al. A Phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma. Blood 106, 2896–2902 (2005).

47 Kaminski, M. S. et al. Radioimmunotherapy of B-cell lymphoma with 131I anti-B1 (anti-CD20) antibody. N. Engl. J. Med. 329, 459–465 (1993). Development of a practical regimen for outpatient therapy of lymphoma with RIT.

48 Horning, S. J. et al. Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J. Clin. Oncol. 23, 712–719 (2005).

49 Goldenberg, D. M., Morschhauser, F. & Wegener, W. A. Veltuzumab (humanized anti-CD20 monoclonal antibody): characterization, current clinical results, and future prospects. Leuk. Lymphoma 51, 747–755 (2010).

50 Davis, T. A. et al. The radioisotope contributes significantly to the activity of radioimmunotherapy. Clin. Cancer Res. 10, 7792–7798 (2004). Documentation of the role of radionuclides in anti-CD20 RIT.

51 Fisher, R. I. et al. Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J. Clin. Oncol. 23, 7565–7573 (2005).

52 Bennett, J. M. et al. Assessment of treatment-related myelodysplastic syndromes and acute myeloid leukemia in patients with non-Hodgkin lymphoma treated with tositumomab and iodine 131I tositumomab. Blood 105, 4576–4582 (2005).

53 Mones, J. V. et al. Dose-attenuated radioimmunotherapy with tositumomab and iodine 131 tositumomab in patients with recurrent non-Hodgkin's lymphoma (NHL) and extensive bone marrow involvement. Leuk. Lymphoma 48, 342–348 (2007).

54 Czuczman, M. S. et al. Treatment-related myelodysplastic syndrome and acute myelogenous leukemia in patients treated with ibritumomab tiuxetan radioimmunotherapy. J. Clin. Oncol. 25, 4285–4292 (2007).

55 Sharkey, R. M., Press, O. W. & Goldenberg, D. M. A re-examination of radioimmunotherapy in the treatment of non-Hodgkin lymphoma: prospects for dual-targeted antibody/radioantibody therapy. Blood 113, 3891–3895 (2009).

56 Johnson, T. A. & Press, O. W. Synergistic cytotoxicity of iodine-131-anti-CD20 monoclonal antibodies and chemotherapy for treatment of B-cell lymphomas. Int. J. Cancer 85, 104–112 (2000).

57 Gopal, A. K. et al. Myeloablative I-131-tositumomab with escalating doses of fludarabine and autologous hematopoietic transplantation for adults age >/= 60 years with B cell lymphoma. Biol. Blood Marrow Transplant 20, 770–775 (2014).

58 Press, O. W. et al. A Phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas. Blood 96, 2934–2942 (2000).

59 Witzig, T. E. et al. Anti-CD22 90Y-epratuzumab tetraxetan combined with anti-CD20 veltuzumab: a Phase I study in patients with relapsed/refractory, aggressive non-Hodgkin lymphoma. Haematologica 99, 1738–1745 (2014).

60 Press, O. W. et al. Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin's lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J. Clin. Oncol. 24, 4143–4149 (2006).

61 Leonard, J. P. et al. Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. J. Clin. Oncol. 23, 5696–5704 (2005).

62 Jacobs, S. A. et al. Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. Clin. Cancer Res. 14, 7088–7094 (2008).

63 Zinzani, P. L. et al. A Phase II trial of CHOP chemotherapy followed by yttrium 90 ibritumomab tiuxetan (Zevalin) for previously untreated elderly diffuse large B-cell lymphoma patients. Ann. Oncol. 19, 769–773 (2008).

64 Zinzani, P. L. et al. Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: a Phase II non-randomised trial (FLUMIZ). Lancet Oncol. 9, 352–358 (2008).

65 Zinzani, P. L. et al. Phase II trial of short-course R-CHOP followed by 90Y-ibritumomab tiuxetan in previously untreated high-risk elderly diffuse large B-cell lymphoma patients. Clin. Cancer Res. 16, 3998–4004 (2010).

66 Zinzani, P. L. et al. A Phase 2 trial of fludarabine and mitoxantrone chemotherapy followed by yttrium-90 ibritumomab tiuxetan for patients with previously untreated, indolent, nonfollicular, non-Hodgkin lymphoma. Cancer 112, 856–862 (2008).

67 Link, B. K. et al. Cyclophosphamide, vincristine, and prednisone followed by tositumomab and iodine-131-tositumomab in patients with untreated low-grade follicular lymphoma: eight-year follow-up of a multicenter Phase II study. J. Clin. Oncol. 28, 3035–3041 (2010).

68 Morschhauser, F. et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J. Clin. Oncol. 26, 5156–5164 (2008).

69 Press, O. W. et al. Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus 131iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J. Clin. Oncol. 31, 314–320 (2013).

70 Husband, J. E. et al. Evaluation of the response to treatment of solid tumours — a consensus statement of the International Cancer Imaging Society. Br. J. Cancer 90, 2256–2260 (2004).

71 Schaefer, N. G., Ma, J., Huang, P., Buchanan, J. & Wahl, R. L. Radioimmunotherapy in non-Hodgkin lymphoma: opinions of U. S. medical oncologists and hematologists. J. Nucl. Med. 51, 987–994 (2010).

72 Matthews, D. C. et al. Phase I study of 131I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome. Blood 94, 1237–1247 (1999).

73 McDevitt, M. R., Finn, R. D., Ma, D., Larson, S. M. & Scheinberg, D. A. Preparation of α-emitting 213Bi-labeled antibody constructs for clinical use. J. Nucl. Med. 40, 1722–1727 (1999).

74 Rosen, S. T. et al. Radioimmunodetection and radioimmunotherapy of cutaneous T cell lymphomas using an 131I-labeled monoclonal antibody: an Illinois Cancer Council Study. J. Clin. Oncol. 5, 562–573 (1987).

75 Zhang, M. et al. The anti-CD25 monoclonal antibody 7G7/B6, armed with the α-emitter 211At, provides effective radioimmunotherapy for a murine model of leukemia. Cancer Res. 66, 8227–8232 (2006).

76 Gopal, A. K., Pagel, J. M., Fromm, J. R., Wilbur, S. & Press, O. W. 131I anti-CD45 radioimmunotherapy effectively targets and treats T-cell non-Hodgkin lymphoma. Blood 113, 5905–5910 (2009).

77 Dietlein, M. et al. Development of anti-CD30 radioimmunoconstructs (RICs) for treatment of Hodgkin's lymphoma. Studies with cell lines and animal studies. Nuklearmedizin 49, 97–105 (2010).

78 Ocean, A. J. et al. Fractionated radioimmunotherapy with (90) Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: a Phase 1 trial. Cancer 118, 5497–5506 (2012).

79 Reardon, D. A. et al. Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: Phase II study results. J. Clin. Oncol. 24, 115–122 (2006).

80 Reardon, D. A. et al. A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost. Neuro Oncol. 10, 182–189 (2008).

81 Zalutsky, M. R. et al. Clinical experience with α-particle-emitting At-211: treatment of recurrent brain tumor patients with At-211-labeled chimeric antitenascin monoclonal antibody 81C6. J. Nuclear Med. 49, 30–38 (2008).

82 Xu, H., Cheung, I. Y., Guo, H. F. & Cheung, N. K. MicroRNA miR-29 modulates expression of immunoinhibitory molecule B7-H3: potential implications for immune based therapy of human solid tumors. Cancer Res. 69, 6275–6281 (2009).

83 Spector, R. & Mock, D. M. Biotin transport and metabolism in the central nervous system. Neurochem. Res. 13, 213–219 (1988).

84 Davson, H. & Segal, M. B. in Physiology of the CSF and Blood–Brain Barriers 489–523 (CRC Press, 1996).

85 Goodwin, D. A., Meares, C. F. & Osen, M. Biological properties of biotin–chelate conjugates for pretargeted diagnosis and therapy with the avidin/biotin system. J. Nucl. Med. 39, 1813–1818 (1998). Initial biotin–avidin for multistep targeting.

86 Rosebrough, S. F. Pharmacokinetics and biodistribution of radiolabeled avidin, streptavidin and biotin. Nucl. Med. Biol. 20, 663–668 (1993).

87 Paganelli, G. et al. Three-step monoclonal antibody tumor targeting in carcinoembryonic antigen-positive patients. Cancer Res. 51, 5960–5966 (1991).

88 Humm, J. L., Chin, L. M. & Macklis, R. M. F(ab')2 fragments versus intact antibody — an isodose comparison. J. Nucl. Med. 31, 1045–1047 (1990).

89 Sharkey, R. M. & Goldenberg, D. M. Advances in radioimmunotherapy in the age of molecular engineering and pretargeting. Cancer Invest. 24, 82–97 (2006).

90 Goldenberg, D. M., Sharkey, R. M., Paganelli, G., Barbet, J. & Chatal, J. F. Antibody pretargeting advances cancer radioimmunodetection and radioimmunotherapy. J. Clin. Oncol. 24, 823–834 (2006). Novel forms of pre-targeting in RIT.

91 Kenanova, V. et al. Radioiodinated versus radiometal-labeled anti-carcinoembryonic antigen single-chain Fv–Fc antibody fragments: optimal pharmacokinetics for therapy. Cancer Res. 67, 718–726 (2007).

92 Larson, S. M. et al. Single chain antigen binding protein (sFv CC49): first human studies in colorectal carcinoma metastatic to liver. Cancer 80, 2458–2468 (1997).

93 Waldmann, T. A. et al. Radioimmunotherapy of interleukin-2R α-expressing adult T-cell leukemia with Yttrium-90-labeled anti-Tac. Blood 86, 4063–4075 (1995).

94 Hnatowich, D. J., Virzi, F. & Rusckowski, M. Investigations of avidin and biotin for imaging applications. J. Nucl. Med. 28, 1294–1302 (1987).

95 Axworthy, D. B. et al. Cure of human carcinoma xenografts by a single dose of pretargeted yttrium-90 with negligible toxicity. Proc. Natl Acad. Sci. USA 97, 1802–1807 (2000). Optimized regimen for streptavidin–biotin multistep targeting of solid tumours, with excellent targeting in vivo with tumour-to-blood therapeutic index of approximately 70, for a reagent that was ultimately introduced into humans.

96 Schultz, J. et al. A tetravalent single-chain antibody–streptavidin fusion protein for pretargeted lymphoma therapy. Cancer Res. 60, 6663–6669 (2000).

97 Paganelli, G. et al. Intraperitoneal radio-localization of tumors pre-targeted by biotinylated monoclonal antibodies. Int. J. Cancer 45, 1184–1189 (1990).

98 Goodwin, D. A. & Meares, C. F. Advances in pretargeting biotechnology. Biotechnol. Adv. 19, 435–450 (2001).

99 Zhang, M. et al. Pretarget radiotherapy with an anti-CD25 antibody–streptavidin fusion protein was effective in therapy of leukemia/lymphoma xenografts. Proc. Natl Acad. Sci. USA 100, 1891–1895 (2003).

100 Press, O. W. et al. A comparative evaluation of conventional and pretargeted radioimmunotherapy of CD20-expressing lymphoma xenografts. Blood 98, 2535–2543 (2001).

101 Pagel, J. M. et al. Comparison of a tetravalent single-chain antibody–streptavidin fusion protein and an antibody–streptavidin chemical conjugate for pretargeted anti-CD20 radioimmunotherapy of B-cell lymphomas. Blood 108, 328–336 (2006).

102 Sharkey, R. M. et al. A universal pretargeting system for cancer detection and therapy using bispecific antibody. Cancer Res. 63, 354–363 (2003).

103 Barbet, J. et al. Pretargeting with the affinity enhancement system for radioimmunotherapy. Cancer Biother. Radiopharm. 14, 153–166 (1999).

104 Gautherot, E. et al. Pretargeted radioimmunotherapy of human colorectal xenografts with bispecific antibody and 131I-labeled bivalent hapten. J. Nucl. Med. 41, 480–487 (2000).

105 Chang, C. H., Rossi, E. A. & Goldenberg, D. M. The dock and lock method: a novel platform technology for building multivalent, multifunctional structures of defined composition with retained bioactivity. Clin. Cancer Res. 13, 5586s–5591s (2007).

106 Rossi, E. A. et al. Stably tethered multifunctional structures of defined composition made by the dock and lock method for use in cancer targeting. Proc. Natl Acad. Sci. USA 103, 6841–6846 (2006).

107 Chmura, A. J., Orton, M. S. & Meares, C. F. Antibodies with infinite affinity. Proc. Natl Acad. Sci. USA 98, 8480–8484 (2001). Multistep targeting with antibodies that bind covalently to the tumour.

108 Butlin, N. G. & Meares, C. F. Antibodies with infinite affinity: origins and applications. Acc. Chem. Res. 39, 780–787 (2006).

109 Orcutt, K. D. et al. A modular IgG-scFv bispecific antibody topology. Protein Eng. Des. Sel. 23, 221–228 (2010). Initial design for a DOTA-based PRIT.

110 Chen, X. et al. Synthesis and in vitro characterization of a dendrimer–MORF conjugate for amplification pretargeting. Bioconjug Chem. 19, 1518–1525 (2008).

111 Liu, X., Wang, Y., Nakamura, K., Kubo, A. & Hnatowich, D. J. Cell studies of a three-component antisense MORF/tat/Herceptin nanoparticle designed for improved tumor delivery. Cancer Gene Ther. 15, 126–132 (2008).

112 Cheal, S. M. et al. Preclinical evaluation of multistep targeting of diasialoganglioside GD2 using an IgG–scFv bispecific antibody with high affinity for GD2 and DOTA metal complex. Mol. Cancer Ther. 13, 1803–1812 (2014).

113 Forero, A. et al. Phase 1 trial of a novel anti-CD20 fusion protein in pretargeted radioimmunotherapy for B-cell non-Hodgkin lymphoma. Blood 104, 227–236 (2004). Initial human trials in lymphoma with multistep targeting based on streptavidin–biotin binding.

114 Forero-Torres, A. et al. Pretargeted radioimmunotherapy (RIT) with a novel anti-TAG-72 fusion protein. Cancer Biother. Radiopharm. 20, 379–390 (2005).

115 Knox, S. J. et al. Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-10 antibody/streptavidin in patients with metastatic colon cancer. Clin. Cancer Res. 6, 406–414 (2000).

116 Kraeber-Bodere, F. et al. Pharmacokinetics and dosimetry studies for optimization of anti-carcinoembryonic antigen x anti-hapten bispecific antibody-mediated pretargeting of Iodine-131-labeled hapten in a phase I radioimmunotherapy trial. Clin. Cancer Res. 9, 3973S–3981S (2003).

117 Aarts, F. et al. Pretargeted radioimmunoscintigraphy in patients with primary colorectal cancer using a bispecific anticarcinoembryonic antigen CEA X anti-di-diethylenetriaminepentaacetic acid F(ab')2 antibody. Cancer 116, 1111–1117 (2010).

118 Vuillez, J. P. et al. Radioimmunotherapy of small cell lung carcinoma with the two-step method using a bispecific anti-carcinoembryonic antigen/anti-diethylenetriaminepentaacetic acid (DTPA) antibody and iodine-131 Di-DTPA hapten: results of a Phase I/II trial. Clin. Cancer Res. 5, 3259s–3267s (1999).

119 Kraeber-Bodere, F. et al. Radioimmunotherapy in medullary thyroid cancer using bispecific antibody and iodine 131-labeled bivalent hapten: preliminary results of a Phase I/II clinical trial. Clin. Cancer Res. 5, 3190s–3198s (1999).

120 Grana, C. et al. Pretargeted adjuvant radioimmunotherapy with yttrium-90-biotin in malignant glioma patients: a pilot study. Br. J. Cancer 86, 207–212 (2002).

121 Walter, R. B., Press, O. W. & Pagel, J. M. Pretargeted radioimmunotherapy for hematologic and other malignancies. Cancer Biother. Radiopharm. 25, 125–142 (2010). General review of the potential and pitfalls of PRIT.

122 Emami, B. et al. Tolerance of normal tissue to therapeutic irradiation. Int. J. Radiat. Oncol. Biol. Phys. 21, 109–122 (1991).

123 Maxon, H. R. et al. Relation between effective radiation dose and outcome of radioiodine therapy for thyroid cancer. N. Engl. J. Med. 309, 937–941 (1983).

124 Larson, S. M. et al. PET scanning of iodine-124-3F9 as an approach to tumor dosimetry during treatment planning for radioimmunotherapy in a child with neuroblastoma. J. Nucl. Med. 33, 2020–2023 (1992). Initial use of PET scanning for dosimetry in humans: initial theranostic applications.

125 Kramer, K. et al. Pharmacokinetics and acute toxicology of intraventricular 131 I-monoclonal antibody targeting disialoganglioside in non-human primates. J. Neurooncol 35, 101–111 (1997).

126 Dobrenkov, K. & Cheung, N. K. GD2-targeted immunotherapy and radioimmunotherapy. Semin. Oncol. 41, 589–612 (2014).

127 Cheung, N. K. et al. Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte–macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. J. Clin. Oncol. 30, 3264–3270 (2012).

128 Cheung, N. K. et al. Single-chain Fv-streptavidin substantially improved therapeutic index in multistep targeting directed at disialoganglioside GD2. J. Nucl. Med. 45, 867–877 (2004).

129 Hainsworth, J. D. et al. Rituximab plus short-duration chemotherapy followed by Yttrium-90 Ibritumomab tiuxetan as first-line treatment for patients with follicular non-Hodgkin lymphoma: a phase II trial of the Sarah Cannon Oncology Research Consortium. Clin. Lymphoma Myeloma 9, 223–228 (2009).

130 Zinzani, P. L. et al. A Phase II trial of short course fludarabine, mitoxantrone, rituximab followed by 90Y-ibritumomab tiuxetan in untreated intermediate/high-risk follicular lymphoma. Ann. Oncol. 23, 415–420 (2012).

131 Morschhauser, F. et al. 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-LineIndolent trial. J. Clin. Oncol. 31, 1977–1983 (2013).

132 Scheinberg, D. A. et al. A Phase I trial of monoclonal antibody M195 in acute myelogenous leukemia: specific bone marrow targeting and internalization of radionuclide. J. Clin. Oncol. 9, 478–490 (1991).

133 Allen, B. J. et al. Analysis of patient survival in a Phase I trial of systemic targeted α-therapy for metastatic melanoma. Immunotherapy 3, 1041–1050 (2011).

134 Allen, B. J. et al. Intralesional targeted α therapy for metastatic melanoma. Cancer Biol. Ther. 4, 1318–1324 (2005).