Antibody-Radionuclide Conjugates for Cancer Therapy: Historical Considerations and New Trends

Abstract

When delivered at a sufficient dose and dose rate to a neoplastic mass, radiation can kill tumor cells. Because cancer frequently presents as a disseminated disease, it is imperative to deliver cytotoxic radiation not only to the primary tumor but also to distant metastases, while reducing exposure of healthy organs as much as possible. Monoclonal antibodies and their fragments, labeled with therapeutic radionuclides, have been used for many years in the development of anticancer strategies, with the aim of concentrating radioactivity at the tumor site and sparing normal tissues. This review surveys important milestones in the development and clinical implementation of radioimmunotherapy and critically examines new trends for the antibody-mediated targeted delivery of radionuclides to sites of cancer.

Radretumab Radioimmunotherapy in Patients with Brain Metastasis: A 124I-L19SIP Dosimetric PET Study

“…In our view, the combination of the chosen antibody format (SIP), isotope ( 124 I), and detection technique (immuno-PET) offers unique advantages over other existing approaches. The L19 antibody in SIP format has been shown to display superior dosimetric and therapeutic properties in mouse models of cancer, compared with the corresponding (scFv) 2 and IgG1 format counterparts (27). The 124 I isotope has a physical half-life (100.2 hours), which matches well with the biologic half-life of proteins in vivo (Figs.…”

“…There is growing interest in the use of "armed" antibodies (i.e., antibodies serving as delivery vehicles for active payloads such as cytotoxic drugs, radionuclides, cytokines, or other immunologic mediators) for therapeutic applications in cancer and in inflammation (1)(2)(3)(4)(5). These pharmaceutical developments rely crucially on the antibody's ability to localize at sites of disease.…”

Selective killing of Kaposi's sarcoma-associated herpesvirus lytically infected cells with a recombinant immunotoxin targeting the viral gpK8.1A envelope glycoprotein

“…This concept, which has been vigorously pursued for decades in the oncology field, exploits three variations of the theme of targeted cytotoxic proteins: 36 (1) antibody-drug conjugates (ADCs) in which mAbs are chemically coupled to low molecular weight cytotoxic compounds, 37,38 (2) radioimmunotherapy whereby radionuclide-conjugated mAbs deliver lethal doses of radiation to the targeted cells, 39,40 and (3) immunotoxins wherein the antigen-binding regions of mAbs are linked (chemically or genetically) to the effector domains of protein toxins typically of bacterial or plant origin. 41,42 The targeted cytotoxic protein approach is receiving increasing attention Complementation of anti-KSHV activity by inhibition of viral DNA replication and targeted killing of infected cells.…”

“…37,38,84 Two radioimmunotherapeutic proteins, ibritumomab tiuxetan (Zevalin ® ) and tositumomab-I131 (Bexxar ® ) are FDA-approved for treatment of certain types of lymphoma; several other radionuclide-conjugated antibodies are advancing in the clinical pipeline. 39,40 In making general comparisons of these approaches, immunotoxins have the disadvantages of relatively short plasma half pTK21.8, 92 previously subjected to sequential single digestion with NdeI (polished with T4 Klenow fragment to generate a blunt end) and HindIII and alkaline-phosphatase treated. The resulting clone was named as 2014-PE38.…”

Application of Radionuclides and Antibody-Drug Conjugates to Target Cancer

“…3 Moreover, this approach is being exploited by several biopharmaceutical companies to develop strategies for delivering radionuclides to image and destroy a variety of cancers including adequate cytotoxic drug payloads. 4 These cytotoxic drug payloads are utilised in the development of Antibody-Drug Conjugates (ADCs) and include the anti-neoplastic agents: Mono Methyl Auristatin E (MMAE) and mertansine (DM1) to target the microtubules in cancerous cells. These other payloads include the DNA damaging agents calicheamicins and duocarmycins extending to the topoisomerase II inhibitors doxorubicins and camptothecins.…”