Radioimmunotherapy (RIT) uses an antibody labeled with a radionuclide to deliver cytotoxic radiation to a target cell. It is a form of unsealed source radiotherapy. In cancer therapy, an antibody with specificity for a tumor-associated antigen is used to deliver a lethal dose of radiation to the tumor cells. The ability for the antibody to specifically bind to a tumor-associated antigen increases the dose delivered to the tumor cells while decreasing the dose to normal tissues. By its nature, RIT requires a tumor cell to express an antigen that is unique to the neoplasm or is not accessible in normal cells.
History of available agents
Name Description FDA status EMA status Ibritumomab tiuxetan (Zevalin) monoclonal antibody anti-CD20 conjugated to a molecule that chelates Yttrium-90. Approved (2002)FIbritumomab Tiuxetan (Zevalin™) Radioimmunotherapy of Non-Hodgkin’s LymphomaRao AV, Akabani G, Rizzieri DA. Radioimmunotherapy for Non-Hodgkin's Lymphoma. Clin Med Res. 2005 Aug;3(3):157-65. Authorised (2004) Iodine (131I) tositumomab (Bexxar) links a molecule containing Iodine-131 to an anti-CD20 monoclonal antibody Approved (2003)Tositumomab and Iodine I 131 Tositumomab – Product Approval Information – Licensing Action Withdrawn (2014) Orphan drug (2003) Withdrawn (2015) Lutetium (177Lu) lilotomab satetraxetan (Betalutin) combination of lutetium-177 and an anti-CD37 monoclonal antibody Fast track (2020) Orphan drug (2020)
131I tositumomab and 90Y ibritumomab tiuxetan were the first agents of radioimmunotherapy, and they were approved for the treatment of refractory non-Hodgkin's lymphoma. This means they are used in patients whose lymphoma is refractory to conventional chemotherapy and the monoclonal antibody rituximab.
Agents in clinical development A set of radioimmunotherapy drugs that rely upon an alpha-emitting isotope (e.g., bismuth-213 or, preferably, actinium-225), rather than a beta emitter, as the killing source of radiation is being developed. Several phase II clinical trials for the treatment of acute myeloid leukemia have been carried out using alpha-emitting RITs.
90Y-FF-21101 is a monoclonal antibody against P-cadherin radiolabeled with yttrium-90. It is one of several RIT treatments under investigation intending to treat solid tumors. A phase I clinical trial began in 2015.A Phase 1 Dose-escalation Study of Radio- Labeled Antibody, FF-21101(90Y) for the Treatment of Advanced Cancer
Other applications (non-approved indications) Other types of cancer for which RIT has therapeutic potential include prostate cancer,Smith-Jones PM. Radioimmunotherapy of prostate cancer. Q J Nucl Med Mol Imaging. 2004 Dec;48(4):297-304. metastatic melanoma,Dadachova E, Nosanchuk JD, Shi L, Schweitzer AD, Frenkel A, Nosanchuk JS, and Casadevall A. Dead cells in melanoma tumors provide abundant antigen for targeted delivery of ionizing radiation by a monoclonal antibody to melanin. Proc Natl Acad Sci USA 2004;101: 14865-70. ovarian cancer,Zalutsky MR, Pozzi OR. Radioimmunotherapy with alpha-particle emitting radionuclides. Q J Nucl Med Mol Imaging. 2004 Dec;48(4):289-96. neoplastic meningitis, leukemia,Burke JM, Jurcic JG. Radioimmunotherapy of leukemia. Adv Pharmacol. 2004;51:185-208. high-grade brain glioma,Quang TS, Brady LW. Radioimmunotherapy as a novel treatment regimen: 125I-labeled monoclonal antibody 425 in the treatment of high-grade brain gliomas. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):972-5. and metastatic colorectal cancer.Wong JY, Shibata S, Williams LE, Kwok CS, Liu A, Chu DZ, Yamauchi DM, Wilczynski S, Ikle DN, Wu AM, Yazaki PJ, Shively JE, Doroshow JH, Raubitschek AA. A Phase I trial of 90Y-anti-carcinoembryonic antigen chimeric T84.66 radioimmunotherapy with 5-fluorouracil in patients with metastatic colorectal cancer. Clin Cancer Res. 2003 Dec 1;9(16 Pt 1):5842-52
Components of the extracellular matrix and the tumor microenvironment can also be targeted by radioimmunotherapy, such as Netrin-1 Kryza D, Wischhusen J, Richaud M, Hervieu M, Sidi Boumedine J, Delcros JG, Besse S, Baudier T, Laval PA, Breusa S, Boutault E, Clermidy H, Rama N, Ducarouge B, Devouassoux-Shisheboran M, Chezal JM, Giraudet AL, Walter T, Mehlen P, Sarrut D, Gibert B.From netrin-1-targeted SPECT/CT to internal radiotherapy for management of advanced solid tumors. EMBO Mol Med. 2023 Apr 11;15(4):e16732. doi: 10.15252/emmm.202216732. Epub 2023 Mar 6. PMID: 36876343 (an axon guidance protein) and FAP (a marker for cancer associated fibroblasts).Marko Magdi Abdou Sidrak, Maria Silvia De Feo, Ferdinando Corica, Joana Gorica, Miriam Conte, Luca Filippi, Orazio Schillaci, Giuseppe De Vincentis, and Viviana Frantellizzi1, Fibroblast Activation Protein Inhibitor (FAPI)-Based Theranostics—Where We Are at and Where We Are Heading: A Systematic Review Int J Mol Sci. 2023 Feb; 24(4): 3863. Published online 2023 Feb 15. doi: 10.3390/ijms24043863
References
External links
Radioimmunotherapy.org