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  • Review Article
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Antibody-targeted radiation cancer therapy

Nature Reviews Drug Discovery volume 3, pages 488–499 (2004)Cite this article

Key Points

  • Increased understanding of the molecular differences between cancer cells and normal cells has led to the development of therapies that target cancer cells, including antibodies directed at tumour-associated antigens. The targeted nature of such therapies offers the promise of greater efficacy and less toxicity, and potentially greater treatment success.

  • Although such antibody therapies have shown significant success in cancer treatment, strategies to increase their efficacy are urgently needed. One such strategy is to link antibodies against tumour-associated antigens to highly toxic radioisotopes, which brings to bear the killing power of these isotopes on tumour cells.

  • In the past two years, the US FDA has approved the use of two radionuclide-based anti-CD20 monoclonal antibody (mAb) regimens for the treatment of NHL — 90Y ibritumomab tiuxetan (Zevalin; Biogen Idec), and tositumomab and 131I tositumomab (Bexxar; Corixa/GlaxoSmithKline) — making further targeted radiation therapy products probable.

  • This review describes radiolabelled-mAb-directed approaches, with an emphasis on the components (protein, radionuclide and chemistry), and discusses clinical trials of radiolabelled mAbs in haematological cancers.

Abstract

Several monoclonal antibodies are now approved for cancer therapy, such as rituximab, an anti-CD20 monoclonal antibody for the treatment of B-cell non-Hodgkin's lymphoma. Such 'naked' antibodies can recruit the body's immune effector mechanisms to kill cells expressing the target of the antibody. In recent years, the linking of radionuclides to antibodies to either augment inherent activity or to exploit the specific targeting properties of monoclonal antibodies has been a major area of development. Two radionuclide-bearing monoclonal antibody therapies have recently been approved by the US FDA, and several more are in clinical trials. Here, we discuss the development and use of radiolabelled monoclonal antibody therapies, with a focus on radiolabelled monoclonal antibodies that have been evaluated in clinical trials.

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Figure 1: A monoclonal antibody linked to a radionuclide.
Figure 2: A representation of the periodic table, highlighting those elements that are of interest for nuclear medicine and radiation oncology applications.
Figure 3: Comparison of path lengths and emission tracks of α- and β−-particle emissions used in antibody-targeted radiation therapy.
Figure 4: A general view of the conjugation of a bifunctional chelating agent to a monoclonal antibody.
Figure 5: Selected examples of bifunctional chelating agents that have been or are currently in antibody-targeted radiation therapy clinical trials.

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Authors and Affiliations

  1. Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, 20892-1002, Maryland, USA

    Diane E. Milenic, Erik D. Brady & Martin W. Brechbiel

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  1. Diane E. Milenic
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DATABASES

Cancer.gov

acute lymphocytic leukaemia

breast cancer

acute myeloid leukaemia

non-Hodgkin's lymphoma

LocusLink

CD20

CD25

CD33

HER2

IL-2

Glossary

SCINTIGRAPHY

Imaging of γ-emissions.

SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY IMAGING

An imaging technique using corrected photon emissions.

CHELATES

A ligand–metal complex.

COORDINATION NUMBER

The number of metal acceptor sites occupied by ligand donors.

METAL-BINDING CHARACTER

Acids (metals) and bases (ligands) can be categorized on the basis of polarizability: 'hard' (less polarizable) metals tend to form stronger complexes with 'hard' ligands than with 'soft' ligands; the converse is also applicable.

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Milenic, D., Brady, E. & Brechbiel, M. Antibody-targeted radiation cancer therapy. Nat Rev Drug Discov 3, 488–499 (2004). https://doi.org/10.1038/nrd1413

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