Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize

Stephen R. Adams, Howard C. Yang, Elamprakash N. Savariar, Joe Aguilera, Jessica L. Crisp, Karra A. Jones, Michael A. Whitney, Scott M. Lippman, Ezra E. W. Cohen, Roger Y. Tsien and Sunil J. Advani ()
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Stephen R. Adams: University of California San Diego
Howard C. Yang: University of California San Diego
Elamprakash N. Savariar: University of California San Diego
Joe Aguilera: University of California San Diego
Jessica L. Crisp: University of California San Diego
Karra A. Jones: University of California San Diego
Michael A. Whitney: University of California San Diego
Scott M. Lippman: University of California San Diego
Ezra E. W. Cohen: University of California San Diego
Roger Y. Tsien: University of California San Diego
Sunil J. Advani: University of California San Diego

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery.

Date: 2016
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DOI: 10.1038/ncomms13019

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