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

Autor: Hingorani DV; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA., Allevato MM; Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA., Camargo MF; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA., Lesperance J; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA., Quraishi MA; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA., Aguilera J; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA., Franiak-Pietryga I; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA., Scanderbeg DJ; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA., Wang Z; Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA., Molinolo AA; Department of Pathology, University of California San Diego, La Jolla, CA, 92093, USA.; UC San Diego, Moores Cancer Center, La Jolla, CA, 92093, USA., Alvarado D; Celldex Therapeutics, Hampton, NJ, 08827, USA., Sharabi AB; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA.; UC San Diego, Moores Cancer Center, La Jolla, CA, 92093, USA., Bui JD; Department of Pathology, University of California San Diego, La Jolla, CA, 92093, USA.; UC San Diego, Moores Cancer Center, La Jolla, CA, 92093, USA., Cohen EEW; UC San Diego, Moores Cancer Center, La Jolla, CA, 92093, USA.; Department of Medicine, Division of Hematology and Oncology, University of California San Diego, La Jolla, CA, 92093, USA., Adams SR; Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA., Gutkind JS; Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA.; UC San Diego, Moores Cancer Center, La Jolla, CA, 92093, USA., Advani SJ; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA. sjadvani@ucsd.edu.; UC San Diego, Moores Cancer Center, La Jolla, CA, 92093, USA. sjadvani@ucsd.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jul 05; Vol. 13 (1), pp. 3869. Date of Electronic Publication: 2022 Jul 05.
DOI: 10.1038/s41467-022-31601-z
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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