Preclinical immunogenicity risk assessment of biotherapeutics using CD4 T cell assays

Robin E Walsh1, Angela Nix1, Chloé Ackaert2

  • 1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States.

PubMed

Insights

Preclinical CD4 T cell assays show limited ability to predict biotherapeutic immunogenicity. Combining multiple assays is crucial for mitigating risks associated with biotherapeutics.

Area of Science:

  • Immunology
  • Biotherapeutics Development
  • Preclinical Assays

Background:

  • T-cell dependent antibody responses to biotherapeutics pose clinical challenges, impacting efficacy and safety.
  • Preclinical CD4 T cell assays are used to predict immunogenicity, but assay variability and poor predictive value are concerns.

Purpose of the Study:

  • To evaluate the predictive performance of three distinct CD4 T cell proliferation assays for biotherapeutic clinical immunogenicity.
  • To assess the utility of different assay formats in identifying potential immunogenic biotherapeutics.

Main Methods:

  • Evaluated a CD8 T cell depleted peripheral blood mononuclear cell (PBMC) assay.
  • Assessed two co-culture assays: dendritic cells (DCs) with autologous CD4 T cells, with and without monocyte restimulation.
  • Used a panel of 10 antibodies with varying clinical immunogenicity.

Main Results:

  • The CD8 T cell depleted PBMC assay predicted immunogenicity for 4 out of 8 highly immunogenic antibodies.
  • DC:CD4 T cell assays detected responses in 5 high-immunogenicity antibodies, but with lower magnitude than PBMC assays.
  • Three highly immunogenic antibodies elicited no response in either assay format.

Conclusions:

  • No single CD4 T cell assay format reliably predicts clinical immunogenicity for all biotherapeutics.
  • Combining diverse preclinical assays, including those for antigen uptake and presentation, is essential for comprehensive immunogenicity risk mitigation.

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