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Complement System: a Neglected Pathway in Immunotherapy.

Anne Bordron1, Cristina Bagacean1,2, Adrian Tempescul1,2

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Monoclonal antibodies (mAbs) leverage the complement system for treating diseases. Understanding complement activation and deficiencies enhances mAb therapy efficacy through various strategies.

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Area of Science:

  • Immunology and Therapeutics
  • Complement System Biology
  • Monoclonal Antibody Engineering

Background:

  • Monoclonal antibodies (mAbs) are approved for autoimmune diseases, hematological malignancies, and solid cancers.
  • The complement system plays a crucial role in the mechanism of action for several mAbs.
  • Complement activation and deficiencies significantly impact mAb therapeutic activity.

Purpose of the Study:

  • To investigate the role of complement activation and deficiencies in monoclonal antibody (mAb) activity.
  • To identify strategies for enhancing the clinical efficacy of mAb therapies.
  • To explore new approaches for optimizing mAb-mediated complement engagement.

Main Methods:

  • Comprehensive investigations using mouse models.
  • In vitro studies assessing complement activation.
  • Patient sample analysis at baseline and post-mAb treatment.

Main Results:

  • Key insights into the importance of complement activation and deficiencies in mAb activity were obtained.
  • Evidence suggests that complement plays a vital role in the efficacy of certain mAb treatments.
  • Patient data revealed basal complement levels and post-treatment impacts of mAbs on the complement system.

Conclusions:

  • New approaches can be developed to increase the clinical efficacy of monoclonal antibodies.
  • Strategies include fresh frozen plasma administration, mAb modifications (e.g., IgG subclass switching, Fc mutations, IgG hexamerization), optimized target recognition for enhanced CDC/CDCC, and control of complement inhibitors.
  • Understanding and manipulating the complement system is critical for advancing mAb-based therapies.