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

Author

Listed:
  • 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
    Moores Cancer Center)

  • Diego Alvarado

    (Celldex Therapeutics)

  • Andrew B. Sharabi

    (University of California San Diego
    Moores Cancer Center)

  • Jack D. Bui

    (University of California San Diego
    Moores Cancer Center)

  • Ezra E. W. Cohen

    (Moores Cancer Center
    University of California San Diego)

  • Stephen R. Adams

    (University of California San Diego)

  • J. Silvio Gutkind

    (University of California San Diego
    Moores Cancer Center)

  • Sunil J. Advani

    (University of California San Diego
    Moores Cancer Center)

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.

Suggested Citation

  • 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. Moli, 2022. "Monomethyl auristatin antibody and peptide drug conjugates for trimodal cancer chemo-radio-immunotherapy," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31601-z
    DOI: 10.1038/s41467-022-31601-z
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