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The development of immunoconjugates for targeted cancer therapy

Key Points

  • Immunoconjugates represent an efficient strategy to exploit the tumor-targeting properties of monoclonal antibodies and the tumor-killing properties of various types of toxins

  • Immunoconjugates are composed of an antibody, a linker and a therapeutic entity

  • Pharmacologics, radioisotopes, and toxins can all be used as therapeutic entity in an immunoconjugate; all three types of therapeutic entities are actively being investigated

  • Future immunoconjugate development will entail the repurposing of existing tumor-targeting antibodies as immunoconjugate delivery vehicles, as well as the design of antibodies with novel tumor-targeting specificities

Abstract

Immunoconjugates are specific, highly effective, minimally toxic anticancer therapies that are beginning to show promise in the clinic. Immunoconjugates consist of three separate components: an antibody that binds to a cancer cell antigen with high specificity, an effector molecule that has a high capacity to kill the cancer cell, and a linker that will ensure the effector does not separate from the antibody during transit and will reliably release the effector to the cancer cell or tumour stroma. The high affinity antibody–antigen interaction allows specific and selective delivery of a range of effectors, including pharmacologic agents, radioisotopes, and toxins, to cancer cells. Some anticancer molecules are not well tolerated when administered systemically owing to unacceptable toxicity to the host. However, this limitation can be overcome through the linking of such cytotoxins to specific antibodies, which mask the toxic effects of the drug until it reaches its target. Conversely, many unconjugated antibodies are highly specific for a cancer target, but have low therapeutic potential and can be repurposed as delivery vehicles for highly potent effectors. In this Review, we summarize the successes and shortcomings of immunoconjugates, and discuss the future potential for the development of these therapies.

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Figure 1: Immunoconjugate modules.
Figure 2: Immunoconjugates structure.
Figure 3: Internalization process.

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Acknowledgements

L.M.W. is supported by National Institute of Health Awards CA51880 and CA50633.

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B.G.S., D.A. and L.M.W. researched data for this article, reviewed and edited the manuscript before submission, provided substantial contribution to discussion of content and wrote the manuscript.

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Correspondence to Louis M. Weiner.

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L.M.W. is an advisor and a consultant for Abbvie, Celldex Pharmaceuticals, Jounce Pharmaceuticals, and Merrimack Pharmaceuticals; he has stock options in Celldex Pharmaceuticals, Jounce Pharmaceuticals and Merrimack Pharmaceuticals and his research has been funded by Symphogen AG. The other authors declare no competing interests.

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Smaglo, B., Aldeghaither, D. & Weiner, L. The development of immunoconjugates for targeted cancer therapy. Nat Rev Clin Oncol 11, 637–648 (2014). https://doi.org/10.1038/nrclinonc.2014.159

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