CLS-logo.png Concept Life Sciences offers a science-led optimization approach for your test substance in determining the most suitable CRA format before performing a screen in a larger donor cohort. 

  • New molecular entities may induce infusion reactions and in turn, lead to cytokine release syndrome (CRS) characterized by a broad inflammatory response and adverse reactions.
  • Following the TeGenero TGN1412 FIH trial that led to 6 volunteers suffering multi-organ failure1, the FDA issued draft guidance on Nonclinical Safety Evaluation of the Immunotoxic Potential of Drugs and Biologics (Feb 2020).
  • There are multiple protocols to test Human cell-based in vitro assays to detect harmful cytokine release and each needs optimizing for each Test Substance2
  • Need to identify the most sensitive model of detection of cytokine release and optimize protocol.


References:

  1. BMJ 2006;332:677 - Learning from the TGN1412 trial 
  2. Findlay, Eastwood, Ball et al. 2011; Comparison of novel methods for predicting the risk of pro-inflammatory clinical infusion reactions during monoclonal antibody therapy. Journal of Immunological Methods, 371, 134-142

Science-led approach - optimization

Our tailored and customized approach ensures a robust experimental design to provide a strong data package and address your scientific questions.

  • Two methods of Test Substance exposure to the biological sample (PBMCs and Whole Blood) are assessed – wet coated onto a plate or applied in aqueous phase.
  • 44 groups for optimization including reference controls Lemtrada® (Alemtuzumab) and Lipopolysaccharide (LPS) known to cause cytokine storm in patients.
  • Th1/Th2 cytokine release profiles are measured using the Multiplex Luminex platform. An exemplar cytokine panel includes GM-CSF, IFN-γ, IL-β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNFα.

Methods of data analysis

For each sample replicate the fold change over vehicle control is calculated, a 2-fold change over vehicle control is considered as relevant. The percentage of responding donors can also be calculated and compared to relevant reference controls.

Using standard assay reference control, Lemtrada® and LPS induce a consistent and widespread cytokine release effect across the donor cohort.

Expert solutions in immune safety assays. Contact us to discuss your challenges.
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