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Technology Insight: cytotoxic drug immunoconjugates for cancer therapy

Nature Clinical Practice Oncology volume 4, pages 245–255 (2007)Cite this article

Abstract

The successful introduction of genetically engineered human and chimeric immunoglobulin proteins has established monoclonal antibodies (mAbs) as a validated approach for treating malignancies. The unique properties of mAb therapies including their high affinity and specificity, and the differential expression of target antigen in tumor cells versus normal cells make them attractive agents for cancer immunotherapy. The field of immunoconjugate development attempts to combine the specificity of mAb therapies with cytotoxic and radionuclide molecules, thereby combining the best characteristics of these two different modalities. Two radiolabeled mAbs, 90Y-ibritumomab tiuxetan and 131I-tositumomab, and one drug conjugate, gemtuzumab ozogamicin have been approved for the treatment of malignancies. Other conjugates carrying toxic payloads of calicheamicin, geldanamycin, maytansinoids and taxoids as well as peptide exotoxins are undergoing preclinical and clinical development. Nevertheless, several obstacles have limited robust antitumor activity and broad application of imunoconjugates, including the optimization of three structural components of the immunoconjugate (i.e. mAb and target specificity, chemical linker design, and the cytotoxin), as well as issues common to mAb therapy such as heterogeneous antigen expression, which can limit uniform antibody delivery. This Review examines optimal design, the lessons learned from clinical immunoconjugate development, and the promising agents in early preclinical/clinical development for the treatment of cancer.

Key Points

  • Immunoconjugates should be viewed as sophisticated delivery systems for antitumor cytotoxic and radionuclide moieties

  • Successful immunoconjugate development requires consideration and optimization of the three major components of the molecule including antibody/antigen target, linker, and payload

  • Biodistribution analysis with radioimmunoconjugates, approved cytotoxic immunoconjugates, or those in development indicate that antigen on circulating cells or circulating shed antigen can profoundly influence toxicity and reduce efficacy

  • Phase II studies indicate that a cytotoxic immunoconjugate (gemtuzumab ozogamicin) can elicit clinically meaningful complete response rates in AML

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Figure 1: Schematic illustration of the three components of an immunoconjugate and examples of antigen targets, linker chemistry, and payloads
Figure 2: Improved biodistribution and localization to lymph nodes with clearance of circulating target antigen expressing cells
Figure 3: Schematic diagram to illustrate the crossfire phenomena and bystander effect

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Acknowledgements

We thank Susan J Knox et al., Clinical Cancer Research and IDEC Pharmaceuticals Corporation for the provision and permission to use Figure 2.

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Authors and Affiliations

  1. AD Ricart is a Postdoctoral Clinical Research Fellow, and AW Tolcher is Director of Clinical Research, at the Institute for Drug Development, Cancer Therapy and Research Center, and a Clinical Professor of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.,

    Alejandro D Ricart & Anthony W Tolcher

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Correspondence to Anthony W Tolcher.

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The authors declared that they have no competing financial interests. AD Ricart and AW Tolcher are investigators in clinical trials with immunoconjugates and Dr. Tolcher has acted as a consultant role to Biogen IDEC, and Genentech.

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Ricart, A., Tolcher, A. Technology Insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Rev Clin Oncol 4, 245–255 (2007). https://doi.org/10.1038/ncponc0774

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