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

  • Nat Commun. 2022 Jul 5;13(1):3869. doi: 10.1038/s41467-022-31601-z.
Dina V Hingorani  #  1 ,  Michael M Allevato  #  2 ,  Maria F Camargo  1 ,  Jacqueline Lesperance  1 ,  Maryam A Quraishi  1 ,  Joseph Aguilera  1 ,  Ida Franiak-Pietryga  1 ,  Daniel J Scanderbeg  1 ,  Zhiyong Wang  2 ,  Alfredo A Molinolo  3  4 ,  Diego Alvarado  5 ,  Andrew B Sharabi  1  4 ,  Jack D Bui  3  4 ,  Ezra E W Cohen  4  6 ,  Stephen R Adams  2 ,  J Silvio Gutkind  2  4 ,  Sunil J Advani  7  8
Affiliations
  • 1. Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA.
  • 2. Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA.
  • 3. Department of Pathology, University of California San Diego, La Jolla, CA, 92093, USA.
  • 4. UC San Diego, Moores Cancer Center, La Jolla, CA, 92093, USA.
  • 5. Celldex Therapeutics, Hampton, NJ, 08827, USA.
  • 6. Department of Medicine, Division of Hematology and Oncology, University of California San Diego, La Jolla, CA, 92093, USA.
  • 7. Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA. [email protected].
  • 8. UC San Diego, Moores Cancer Center, La Jolla, CA, 92093, USA. [email protected].
  • # Contributed equally.
PMID: 35790753 DOI: 10.1038/s41467-022-31601-z
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.

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