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Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
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Fc Effector Function of Immune Checkpoint Blocking Antibodies in Oncology

Romane Martineau1,2, Sandrine Susini2,3, Aurelien Marabelle1,2,3

  • 1Université Paris Saclay, Le Kremlin-Bicetre, France.

Immunological Reviews
|December 12, 2024
PubMed

Insights

Monoclonal antibodies targeting immune checkpoints like CTLA-4 and PD-1 can treat cancer. Their effectiveness depends on interactions with Fc gamma receptors (FcγR), influencing safety and efficacy in oncology.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Antagonistic monoclonal antibodies (mAbs) targeting immune checkpoints have transformed cancer treatment.
  • Key checkpoints include CTLA-4, PD-1, and LAG3, which regulate T cell responses.
  • FDA/EMA approved antibodies target these checkpoints, with varying mechanisms and Fc gamma receptor (FcγR) affinities.

Purpose of the Study:

  • To review the impact of FcγR effector functions on the safety and efficacy of immune checkpoint blockers.
  • To elucidate how FcγR interactions influence the therapeutic outcomes of monoclonal antibodies in oncology.

Main Methods:

  • Review of existing literature on monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1.
  • Analysis of antibody isotypes (IgG1, IgG2a, IgG4) and their FcγR binding affinities.
  • Examination of antibody effector functions such as Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP).

Main Results:

  • Anti-CTLA-4 (ipilimumab, tremelimumab) and some anti-PD-L1 (avelumab) antibodies possess high FcγR affinity, enabling ADCC/ADCP crucial for in vivo efficacy.
  • Anti-PD(L)1 antibodies (nivolumab, pembrolizumab, durvalumab, atezolizumab) are engineered for low FcγR affinity to optimize pure checkpoint blockade.
  • FcγR effector function significantly correlates with the safety and efficacy profiles of these cancer immunotherapies.

Conclusions:

  • FcγR effector function is a critical determinant of immune checkpoint blocker performance in cancer therapy.
  • Tailoring FcγR affinity is essential for optimizing the therapeutic index of monoclonal antibodies targeting immune checkpoints.
Keywords:
FcγRimmune checkpointmonoclonal antibody

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