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Arming antibodies: prospects and challenges for immunoconjugates

Abstract

Immunoconjugates—monoclonal antibodies (mAbs) coupled to highly toxic agents, including radioisotopes and toxic drugs (ineffective when administered systemically alone)—are becoming a significant component of anticancer treatments. By combining the exquisite targeting specificity of mAbs with the enhanced tumor-killing power of toxic effector molecules, immunoconjugates permit sensitive discrimination between target and normal tissue, resulting in fewer toxic side effects than most conventional chemotherapeutic drugs. Two radioimmunoconjugates, ibritumomab tiuxetan (Zevalin) and tositumomab-131I (Bexxar), and one drug conjugate, gemtuzumab ozogamicin (Mylotarg), are now on the market. For the next generation of immunoconjugates, advances in protein engineering will permit greater control of mAb targeting, clearance and pharmacokinetics, resulting in significantly improved delivery to tumors of radioisotopes and potent anticancer drugs. Pretargeting strategies, which separate the two functions of antibody-based localization and delivery or generation of the toxic agent into two steps, also promise to afford superior tumor targeting and therapeutic efficacy. Several challenges in optimizing immunoconjugates remain, however, including poor intratumoral mAb uptake, normal tissue conjugate exposure and issues surrounding drug potency and conditional release from mAb carriers. Nonetheless, highly promising results from preclinical models will continue to drive the clinical development of this therapeutic class.

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Figure 1: Relationship between engineered antibody format, targeting and imaging, and blood clearance.

Katie Ris

Figure 2: Chemical structures of some advanced mAb-drug conjugates.

Katie Ris

Figure 3: Pretargeting technologies for mAb-mediated delivery of cytotoxic agents to tumor cells.

Katie Ris

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Acknowledgements

The authors are grateful to their many colleagues and collaborators who have contributed over the years to the fields of antibody engineering and immunoconjugates. Apologies are extended to any authors whose work has not been included as a result of lack of space. Work in Anna Wu's laboratory was supported by NIH CA43904, CA86306, CA92131, DAMD 17-00-1-150 and DAMD 17-00-1-203. Work in Peter Senter's laboratory was partially supported by NIH CA088583.

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Wu, A., Senter, P. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol 23, 1137–1146 (2005). https://doi.org/10.1038/nbt1141

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