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CRISPR-Cas9 screens identify regulators of antibody-drug conjugate toxicity

C Kimberly Tsui1, Robyn M Barfield2, Curt R Fischer3

  • 1Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Nature Chemical Biology
|August 28, 2019
PubMed

Insights

Researchers identified new regulators of antibody-drug conjugate (ADC) toxicity and delivery. Sialic acid depletion enhances ADC efficacy, offering new strategies for cancer therapy.

Area of Science:

  • Oncology
  • Cell Biology
  • Pharmacology

Background:

  • Antibody-drug conjugates (ADCs) are crucial cancer therapeutics that deliver chemotherapy to target cells.
  • The precise mechanisms of ADC internalization and activation are not fully understood.
  • Identifying regulators of these processes can optimize ADC therapy.

Purpose of the Study:

  • To uncover novel regulators of endolysosomal trafficking involved in ADC toxicity.
  • To elucidate the role of specific endolysosomal proteins in ADC activation.
  • To explore strategies for enhancing ADC delivery and efficacy.

Main Methods:

  • CRISPR-Cas9 screening to identify genetic modulators of ADC toxicity.
  • Comparative analysis of ADCs with varying linker chemistries.
  • Investigation of lysosomal delivery pathways and sialic acid's role.

Main Results:

  • Discovered known and novel endolysosomal regulators impacting ADC toxicity, including C18ORF8/RMC1 in endosomal maturation.
  • Demonstrated that late endolysosomal regulators selectively affect non-cleavable linker ADCs.
  • Found that cleavable valine-citrulline linkers can be processed independently of lysosomal delivery.
  • Showed sialic acid depletion enhances ADC lysosomal delivery and cancer cell killing, including for trastuzumab emtansine (T-DM1).

Conclusions:

  • New regulators of endolysosomal trafficking in ADC pathways have been identified.
  • Insights into linker chemistry and endolysosomal regulation can guide future ADC design.
  • Sialic acid modulation presents a potential strategy to improve ADC-based cancer treatments.

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