Monomethyl auristatin antibody and peptide drug conjugates for trimodal cancer chemo-radio-immunotherapy

Dina V. Hingorani, Michael M. Allevato, Maria F. Camargo, Jacqueline Lesperance, Maryam A. Quraishi, Joseph Aguilera, Ida Franiak-Pietryga, Daniel J. Scanderbeg, Zhiyong Wang, Alfredo A. Molinolo, Diego Alvarado, Andrew B. Sharabi, Jack D. Bui, Ezra E. W. Cohen, Stephen R. Adams, J. Silvio Gutkind and Sunil J. Advani ()
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Dina V. Hingorani: University of California San Diego
Michael M. Allevato: University of California San Diego
Maria F. Camargo: University of California San Diego
Jacqueline Lesperance: University of California San Diego
Maryam A. Quraishi: University of California San Diego
Joseph Aguilera: University of California San Diego
Ida Franiak-Pietryga: University of California San Diego
Daniel J. Scanderbeg: University of California San Diego
Zhiyong Wang: University of California San Diego
Alfredo A. Molinolo: University of California San Diego
Diego Alvarado: Celldex Therapeutics
Andrew B. Sharabi: University of California San Diego
Jack D. Bui: University of California San Diego
Ezra E. W. Cohen: Moores Cancer Center
Stephen R. Adams: University of California San Diego
J. Silvio Gutkind: University of California San Diego
Sunil J. Advani: University of California San Diego

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Locally advanced cancers remain therapeutically challenging to eradicate. The most successful treatments continue to combine decades old non-targeted chemotherapies with radiotherapy that unfortunately increase normal tissue damage in the irradiated field and have systemic toxicities precluding further treatment intensification. Therefore, alternative molecularly guided systemic therapies are needed to improve patient outcomes when applied with radiotherapy. In this work, we report a trimodal precision cytotoxic chemo-radio-immunotherapy paradigm using spatially targeted auristatin warheads. Tumor-directed antibodies and peptides conjugated to radiosensitizing monomethyl auristatin E (MMAE) specifically produce CD8 T cell dependent durable tumor control of irradiated tumors and immunologic memory. In combination with ionizing radiation, MMAE sculpts the tumor immune infiltrate to potentiate immune checkpoint inhibition. Here, we report therapeutic synergies of targeted cytotoxic auristatin radiosensitization to stimulate anti-tumor immune responses providing a rationale for clinical translational of auristatin antibody drug conjugates with radio-immunotherapy combinations to improve tumor control.

Date: 2022
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DOI: 10.1038/s41467-022-31601-z

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