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Toward a Ferrous Iron-Cleavable Linker for Antibody-Drug Conjugates

Benjamin Spangler1, Toni Kline2, Jeffrey Hanson2

  • 1Graduate Program in Chemistry & Chemical Biology , University of California , San Francisco , California 94143 , United States.

Molecular Pharmaceutics
|March 24, 2018
PubMed

Insights

Novel antibody-drug conjugates (ADCs) utilize a unique TRX linker for targeted cancer therapy. This linker demonstrates tumor selectivity and potent payload release, minimizing off-target effects for improved therapeutic windows.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Antibody-drug conjugates (ADCs) offer targeted cancer therapy by delivering cytotoxic payloads.
  • Current ADCs face limitations due to internalization in non-target cells, restricting therapeutic efficacy.
  • Development of selective linkers is crucial to minimize off-target toxicity and enhance therapeutic windows.

Purpose of the Study:

  • To develop and evaluate a novel ADC linker based on an Fe(II)-reactive 1,2,4-trioxolane scaffold (TRX).
  • To assess the tumor-selective activity and payload release of TRX-linked ADCs.
  • To compare the efficacy of TRX-ADCs with conventional ADCs in preclinical cancer models.

Main Methods:

  • Site-selective conjugation of TRX linkers to trastuzumab.
  • In vitro assessment of ADC activity in HER2-positive and HER2-negative cancer cells.
  • Comparison of TRX-ADC efficacy against ADCs with established linker chemistries.

Main Results:

  • TRX-linked ADCs demonstrated efficient payload release upon cellular uptake.
  • Picomolar potencies were achieved in antigen-positive cancer cells.
  • A destabilizing interaction between TRX linkers and antibody residues was identified, suggesting areas for design improvement.

Conclusions:

  • The TRX linker exhibits potential for tumor-selective ADC development.
  • Further optimization of TRX linker design is warranted to enhance stability and efficacy.
  • TRX-based ADCs represent a promising strategy for targeted cancer therapy with reduced collateral damage.
Keywords:
1,2,4-trioxolanesantibody−drug conjugatescancerlabile irontargeted drug deliverytraceless linker chemistry

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