Key Points
-
Antibodies with practical healthcare applications are being introduced into modern medicine at a rapid pace by academic laboratories and industry. Therapeutic applications of these biologics are becoming increasingly important for cancer, either by promoting the body's own defence against the tumour or as a carrier for immunotoxins, drugs or radiation.
-
Radioimmunotherapy, which is the subject of this Review, exploits the immune protein as a carrier for radioactive isotopes, tracers or targeted therapeutics. The radioantibody is introduced into the blood or a body cavity such as the peritoneum, pleura or intrathecal space, and is carried to its natural target or antigen-binding site on the tumour cell by blood flow, diffusion or the bulk flow of fluid.
-
Cancer cells naturally produce cancer-associated biological molecules, which are adaptive features of malignant change that are suitable as antigenic binding sites owing to their relatively high abundance in cancer cells in comparison to normal tissues. These cancer-associated antigens may be located in the membrane, cytoplasm or organelles, including the nucleus. Typical concentrations of target antigens are in the nanomolar to low micromolar range.
-
Cancer-selective antibodies and related immunoproteins are particularly well suited for conjugation with radioisotopes, for the purpose of detection or targeted radiotherapy. As a rule of thumb, the concentration of antibody at the binding site should approximate but not exceed the concentration of antigen (that is, the nanomolar range), and this amount of carrier is enormous relative to the required concentrations of attached radioisotopes for detection or therapy. This is because radioisotopes are among the most energetic moieties known, and this energy can be used for imaging or radiotherapy when attached to antibodies, in the femto-molar to pico-molar range.
Abstract
The eradication of cancer remains a vexing problem despite recent advances in our understanding of the molecular basis of neoplasia. One therapeutic approach that has demonstrated potential involves the selective targeting of radionuclides to cancer-associated cell surface antigens using monoclonal antibodies. Such radioimmunotherapy (RIT) permits the delivery of a high dose of therapeutic radiation to cancer cells, while minimizing the exposure of normal cells. Although this approach has been investigated for several decades, the cumulative advances in cancer biology, antibody engineering and radiochemistry in the past decade have markedly enhanced the ability of RIT to produce durable remissions of multiple cancer types.
Similar content being viewed by others
Change history
24 July 2015
Nai-Kong V. Cheung and Steven M. Larson have now declared competing interests that were not stated in the version of this article that was originally published. The following competing interests statement has now been added to the online version: "S.M.L. has ownership interest (including patents) in nanoparticle constructs of C-DOTs, use of mAB A33, and small molecular radio label drugs in Dasatinib and the HSP 90 inhibitor PUH71 and kinetics of immunoPET localization to tumours. N.-K.V.C. has ownership interest (including patents) in scfv constructs of anti-GD2 antibodies, therapy-enhancing glucan, use of mAb 8H9, methods for preparing and using scFv, GD2 peptide mimics, methods for detecting MRD, anti-GD2 antibodies, generation and use of HLA-A2-restricted peptide-specific mAbs and CARs, high-affinity anti-GD2 antibodies, multimerization technologies, bispecific HER2 and CD3 binding molecules, affinity matured hu8H9, anti-chondroitin sulfate proteoglycan 4 antibodies and uses thereof, and ROR2 antibodies. J.A.C. and O.W.P. declare no competing interests.".
References
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).
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.
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.
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.
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).
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).
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).
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).
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).
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.
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).
Tedder, T. F. & Engel, P. CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol. Today 15, 450–454 (1994).
Chang, K. L., Arber, D. A. & Weiss, L. M. CD20: a review. Appl. Immunohistochem. 4, 1–15 (1996).
Press, O. W. Radioimmunotherapy for non-Hodgkin's lymphomas: a historical perspective. Semin. Oncol. 30, 10–21 (2003).
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.
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).
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.
Geissler, F., Anderson, S. K. & Press, O. Intracellular catabolism of radiolabeled anti-CD3 antibodies by leukemic T cells. Blood 78, 1864–1874 (1991).
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).
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).
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).
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).
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).
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.
Jurcic, J. G. et al. Targeted α particle immunotherapy for myeloid leukemia. Blood 100, 1233–1239 (2002). Early work with 225Ac.
Hall, E. J. & Giaccia, A. J. Radiobiology for the Radiologist (Lippincott Williams & Wilkins, 2005).
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).
Zalutsky, M. R. & Pozzi, O. R. Radioimmunotherapy with α-particle emitting radionuclides. Q. J. Nucl. Med. Mol. Imaging 48, 289–296 (2004).
Couturier, O. et al. Cancer radioimmunotherapy with α-emitting nuclides. Eur. J. Nucl. Med. Mol. Imaging 32, 601–614 (2005).
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.
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).
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).
Dahle, J. et al. Targeted cancer therapy with a novel low-dose rate α-emitting radioimmunoconjugate. Blood 110, 2049–2056 (2007).
Waldmann, T. ABCs of radioisotopes used for radioimmunotherapy: α- and β-emitters. Leuk. Lymphoma 44 (Suppl. 3), S107–S113 (2003).
He, P. et al. Two-compartment model of radioimmunotherapy delivered through cerebrospinal fluid. Eur. J. Nucl. Med. Mol. Imaging 38, 334–342 (2011).
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.
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.
Kramer, K. B. et al. ANR Congress. ANR Congress [online], (2014).
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.
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.
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.
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.
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).
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).
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).
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).
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.
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Spector, R. & Mock, D. M. Biotin transport and metabolism in the central nervous system. Neurochem. Res. 13, 213–219 (1988).
Davson, H. & Segal, M. B. in Physiology of the CSF and Blood–Brain Barriers 489–523 (CRC Press, 1996).
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.
Rosebrough, S. F. Pharmacokinetics and biodistribution of radiolabeled avidin, streptavidin and biotin. Nucl. Med. Biol. 20, 663–668 (1993).
Paganelli, G. et al. Three-step monoclonal antibody tumor targeting in carcinoembryonic antigen-positive patients. Cancer Res. 51, 5960–5966 (1991).
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).
Sharkey, R. M. & Goldenberg, D. M. Advances in radioimmunotherapy in the age of molecular engineering and pretargeting. Cancer Invest. 24, 82–97 (2006).
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.
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).
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).
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).
Hnatowich, D. J., Virzi, F. & Rusckowski, M. Investigations of avidin and biotin for imaging applications. J. Nucl. Med. 28, 1294–1302 (1987).
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.
Schultz, J. et al. A tetravalent single-chain antibody–streptavidin fusion protein for pretargeted lymphoma therapy. Cancer Res. 60, 6663–6669 (2000).
Paganelli, G. et al. Intraperitoneal radio-localization of tumors pre-targeted by biotinylated monoclonal antibodies. Int. J. Cancer 45, 1184–1189 (1990).
Goodwin, D. A. & Meares, C. F. Advances in pretargeting biotechnology. Biotechnol. Adv. 19, 435–450 (2001).
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).
Press, O. W. et al. A comparative evaluation of conventional and pretargeted radioimmunotherapy of CD20-expressing lymphoma xenografts. Blood 98, 2535–2543 (2001).
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).
Sharkey, R. M. et al. A universal pretargeting system for cancer detection and therapy using bispecific antibody. Cancer Res. 63, 354–363 (2003).
Barbet, J. et al. Pretargeting with the affinity enhancement system for radioimmunotherapy. Cancer Biother. Radiopharm. 14, 153–166 (1999).
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).
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).
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).
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.
Butlin, N. G. & Meares, C. F. Antibodies with infinite affinity: origins and applications. Acc. Chem. Res. 39, 780–787 (2006).
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.
Chen, X. et al. Synthesis and in vitro characterization of a dendrimer–MORF conjugate for amplification pretargeting. Bioconjug Chem. 19, 1518–1525 (2008).
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).
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).
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.
Forero-Torres, A. et al. Pretargeted radioimmunotherapy (RIT) with a novel anti-TAG-72 fusion protein. Cancer Biother. Radiopharm. 20, 379–390 (2005).
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).
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).
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).
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).
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).
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).
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.
Emami, B. et al. Tolerance of normal tissue to therapeutic irradiation. Int. J. Radiat. Oncol. Biol. Phys. 21, 109–122 (1991).
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).
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.
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).
Dobrenkov, K. & Cheung, N. K. GD2-targeted immunotherapy and radioimmunotherapy. Semin. Oncol. 41, 589–612 (2014).
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).
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).
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).
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).
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).
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).
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).
Allen, B. J. et al. Intralesional targeted α therapy for metastatic melanoma. Cancer Biol. Ther. 4, 1318–1324 (2005).
Raja, C. et al. Interim analysis of oxicity and response in Phase 1 trial of systemic targeted α therapy for metastatic melanoma. Cancer Biol. Ther. 6, 846–852 (2007).
Acknowledgements
This study was supported in part by the Center for Targeted Radioimmunotherapy and Theranostics, USA, and the Ludwig Center for Cancer Immunotherapy, USA. Additional financial support was provided by the Donna and Benjamin M. Rosen Chair and the Enid A. Haupt Chair (for S.M.L. and N.K.C., respectively). O.W.P. was supported in part by NCI PO1 CA044991, NCI R01 CA076287, NIH R01 CA109663, NCI R01 CA136639, NCI R01 CA154897 and NCI R01 CA138720. S.M.L. was also supported in part by NCI P50-CA86438 and Sloan Kettering Institute, USA. The authors wish to thank D. A. Scheinberg, J. D. Wolchok and W. A. Weber for their valuable contributions to this research.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
Nai-Kong V. Cheung and Steven M. Larson have now declared competing interests that were not stated in the version of this article that was originally published. The following competing interests statement has now been added to the online version: "S.M.L. has ownership interest (including patents) in nanoparticle constructs of C-DOTs, use of mAB A33, and small molecular radio label drugs in Dasatinib and the HSP 90 inhibitor PUH71 and kinetics of immunoPET localization to tumours. N.-K.V.C. has ownership interest (including patents) in scfv constructs of anti-GD2 antibodies, therapy-enhancing glucan, use of mAb 8H9, methods for preparing and using scFv, GD2 peptide mimics, methods for detecting MRD, anti-GD2 antibodies, generation and use of HLA-A2-restricted peptide-specific mAbs and CARs, high-affinity anti-GD2 antibodies, multimerization technologies, bispecific HER2 and CD3 binding molecules, affinity matured hu8H9, anti-chondroitin sulfate proteoglycan 4 antibodies and uses thereof, and ROR2 antibodies. J.A.C. and O.W.P. declare no competing interests."
Related links
Supplementary information
41568_2015_BFnrc3925_MOESM7_ESM.pdf
Supplementary information S1 (table) | Characteristics of selected α and β emitters used in radioimmunotherapy (RIT) applications1,2,3 (PDF 127 kb)
Glossary
- Theranostics
-
A chemical moiety that can be used for both therapy and diagnostic purposes; for example, radioisotopes of iodine, 131I and 124I, can be used for both quantitative nuclear imaging and therapy.
- Dosimetry
-
Assessment (by measurement or calculation) of radiation dose.
- Therapeutic index
-
The ratio between the dosage of a drug that causes a major therapeutic effect and the dosage that causes a toxic effect; in radioimmunotherapy, this is the ratio of radiation-absorbed dose to the tumour divided by the dose to a radiosensitive tissue such as kidney or bone marrow.
- Bystander effect
-
The phenomenon in which radiation affects neighbouring cells in addition to cells at the site of targeting.
- Residualized
-
A radioactive form that is trapped in the tumour cell after catabolism of an internalized antigen–antibody complex; some non-residualizing radionuclides can be made residualizing through the use of specific chemical constructs that limit catabolism.
- Path length
-
The actual distance that a nuclear particle travels in tissue as part of the process of radioactive decay.
- β-particles
-
Electron-like negative particles emitted from the nuclei of β-emitting radionuclides.
- α-particles
-
Particles the size of a helium nucleus made up of two protons and two neutrons, produced by α-emitting radionuclides (for example, 225Ac).
- Bremsstrahlung
-
A type of electromagnetic radiation produced when a high-energy charged particle is decelerated or deflected by another charged particle.
- Myelosuppression
-
A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells and platelets.
- Cardiopulmonary toxicities
-
Adverse effects on the blood systems, heart or lungs, resulting from exposure to toxic chemicals, for example, cardiac ischaemia, pulmonary inflammation and an increased level of toxins in the blood.
- Linear energy transfer
-
(LET). The action of radiation on matter that describes how much energy an ionizing particle transfers to the material transversed per unit distance.
- Half-life
-
The characteristic period of decay during which half of the population of radioactive atoms will undergo spontaneous radioactive decay.
- Leptomeninges
-
The two innermost layers of tissue (arachnoid mater and pia mater) that cover the brain and spinal cord.
- Ommaya reservoir
-
A device surgically placed under the scalp and used to deliver anticancer drugs to the cerebrospinal fluid.
- Human anti-mouse antibodies
-
(HAMAs). Antibodies found in humans that react to immunoglobins found in mice.
- Convention-enhanced delivery
-
A therapy in which therapeutic compounds are forced directly into the region of interest through a needle or cannula by applying a low-pressure gradient.
- Haptens
-
Small molecules that, when combined with larger carriers such as a protein, can elicit the production of antibodies that bind specifically to them (in the free or combined states).
- Bispecific antibodies
-
Artificial proteins composed of fragments of two different monoclonal antibodies, which consequently bind to two different types of antigen.
- Fragment antigen-binding fragments
-
(Fab fragments). Regions on an antibody that bind to antigens and that are composed of one constant and one variable domain of each of the heavy and the light chains.
- DOTA
-
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. DOTA functions as a chelating agent for the radioisotope 90Y3+ or other radiometals. It can be conjugated to monoclonal antibodies by attachment of one of the four carboxyl groups as an amide.
- Single-chain variable fragment
-
(scFv). A fusion protein of the variable regions of the heavy (VH) and light (VL) chains of immunoglobulins, connected with a short linker peptide of ∼10–25 amino acids.
- Phosphorodiamidate morpholino oligomers
-
(MORFs). A family of synthetic oligomers that are water soluble and reported to be stable both in vitro and in vivo.
- Area under the curve
-
(AUC). The overall amount of drug in the bloodstream or other tissue after a dose.
Rights and permissions
About this article
Cite this article
Larson, S., Carrasquillo, J., Cheung, NK. et al. Radioimmunotherapy of human tumours. Nat Rev Cancer 15, 347–360 (2015). https://doi.org/10.1038/nrc3925
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrc3925
- Springer Nature Limited
This article is cited by
-
Functional hydrogels for hepatocellular carcinoma: therapy, imaging, and in vitro model
Journal of Nanobiotechnology (2024)
-
MIB Guides: Preclinical Radiopharmaceutical Dosimetry
Molecular Imaging and Biology (2024)
-
Intricacies in the Preparation of Patient Doses of [177Lu]Lu-Rituximab and [177Lu]Lu-Trastuzumab Using Low Specific Activity [177Lu]LuCl3: Methodological Aspects
Molecular Imaging and Biology (2024)
-
Therapeutic efficacy of an alpha-particle emitter labeled anti-GD2 humanized antibody against osteosarcoma—a proof of concept study
European Journal of Nuclear Medicine and Molecular Imaging (2024)
-
New opportunities for RGD-engineered metal nanoparticles in cancer
Molecular Cancer (2023)