Inhibition of Complement Regulators Sensitizes Tumor Cells to Complement Attack

Strategic Insights -

Tumor cell lines resistant to complement attack overexpress membrane-bound complement regulatory proteins, limiting the efficacy of cancer immunotherapy. Researchers from Heidelberg, Germany, designed small interfering RNAs (siRNAs) to knock down these regulators and enhance complement-dependent cytotoxicity. They demonstrated that siRNA-induced inhibition of complement regulators significantly sensitized tumor cells to complement attack, augmenting cytotoxicity and potentially improving antibody-based cancer immunotherapy.

Key Takeaways:

  • The efficacy of cancer-immunotherapy with complement-activating monoclonal antibodies is limited by over-expression of membrane-bound complement regulatory proteins (mCRPs: CD46, CD55, CD59) on the surface of neoplastic cells.
  • siRNA anti-CD46(301) reduced CD46 protein expression up to 80%, siRNA anti-CD55(255) diminished CD55 protein expression up to 49%, and CD59 protein expression was inhibited up to 82% by siRNA anti-CD59(1339).
  • Time course experiments revealed a long-lasting silencing effect with 50% complement regulator inhibition up to day 13.
  • Upon mCRP knock down, complement-dependent cytotoxicity (CDC) was augmented by 20-30% for CD46, by up to 24% for CD55, and by up to 55% for CD59.
  • The combined inhibition of all three inhibitors further enhanced CDC by up to 66%.
  • CD46 and CD55 downregulation increased significantly C3 osponization, which supports cell-mediated defense mechanisms.
  • mCRP blocking antibodies were only partly able to further augment the tumor cells' susceptibility to complement lysis.

Statistics:

  • Up to 80% reduction in CD46 protein expression by siRNA anti-CD46(301)
  • Up to 49% reduction in CD55 protein expression by siRNA anti-CD55(255)
  • Up to 82% inhibition of CD59 protein expression by siRNA anti-CD59(1339)
  • 50% complement regulator inhibition up to day 13
  • 20-30% augmentation of CDC for CD46
  • Up to 24% augmentation of CDC for CD55
  • Up to 55% augmentation of CDC for CD59
  • Up to 66% enhancement of CDC with combined inhibition of all three inhibitors
  • Significant increase in C3 osponization following CD46 and CD55 downregulation

Sources:

  • (Geis et al., 2010) - "Inhibition of membrane complement inhibitor expression (CD46, CD55, CD59) by siRNA sensitizes tumor cells to complement attack in vitro. Current Cancer Drug Targets, 2010;10(8):922-31"
  • (University of Heidelberg, Institute of Immunology)