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Anticancer carrier-linked prodrugs in clinical trials

Felix Kratz1, Khalid Abu Ajaj, André Warnecke

  • 1Tumor Biology Center, Macromolecular Prodrugs, Freiburg, Germany. felix@tumorbio.uni-freiburg.de

Expert Opinion on Investigational Drugs
|June 28, 2007
PubMed

Insights

Attaching anticancer drugs to larger molecules like antibodies or polymers improves treatment effectiveness and reduces side effects. This review covers clinical studies of these macromolecular prodrugs, including antibody-drug conjugates.

Area of Science:

  • Oncology
  • Pharmacology
  • Bioconjugation Chemistry

Background:

  • Attaching low molecular weight anticancer drugs to macromolecules like antibodies, serum proteins, or polymers via cleavable linkers enhances the therapeutic index of cytotoxic agents.
  • Modern antibody-drug conjugates (ADCs) utilize highly potent drugs (e.g., calicheamicin, maytansins) and have advanced to clinical trials.
  • Gemtuzumab ozogamicin, an ADC combining calicheamicin with an anti-CD33 antibody, represents a significant milestone as the first approved ADC.

Purpose of the Study:

  • To review and summarize Phase I-III clinical studies of macromolecular prodrugs.
  • To provide an overview of various drug conjugate platforms evaluated in clinical trials.
  • To highlight the therapeutic advancements and challenges associated with these novel drug delivery systems.

Main Methods:

  • Review of published Phase I-III clinical trial data for macromolecular prodrugs.
  • Categorization of drug conjugates based on the carrier molecule (antibodies, polymers, proteins) and drug payload.
  • Analysis of clinical outcomes, including efficacy and toxicity, for different conjugate types.

Main Results:

  • Several drug conjugate platforms have undergone clinical assessment, including N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates (doxorubicin, camptothecin, paclitaxel, Pt(II) complexes), poly(ethylene glycol) conjugates (camptothecin, paclitaxel), polyglutamate conjugates (paclitaxel, camptothecin), methotrexate-albumin conjugates, and albumin-binding doxorubicin prodrugs.
  • Gemtuzumab ozogamicin, an anti-CD33 ADC, has received market approval, demonstrating the clinical viability of ADCs.
  • Various macromolecular prodrugs have shown promise in improving drug delivery and therapeutic outcomes in oncology.

Conclusions:

  • Macromolecular prodrugs, particularly ADCs, represent a promising strategy for enhancing cancer therapy by improving drug targeting and reducing systemic toxicity.
  • The clinical success of Gemtuzumab ozogamicin validates the ADC approach.
  • Continued research and clinical evaluation of diverse macromolecular prodrugs are essential for advancing cancer treatment paradigms.

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