Examining Hypersensitivity Reactions Early in Drug Development using a High-throughput In Vitro Assay

This blog takes a look at the recent work Cyprotex has done in the field of immunotoxicology prediction and the poster we presented at the 61st Annual Society of Toxicology Meeting (SOT) and ToxExpo, March 27-31, 2022.

Drug hypersensitivity is a rare, idiosyncratic and immune-mediated adverse reaction that targets several organs including the liver, skin and blood, and can result in morbidity and occasional mortality in susceptible individuals. These reactions are off-target, difficult to predict and constitute a major challenge to patients, their clinicians and the pharmaceutical industry. Therefore, predictive screening of candidate drugs for immunotoxicity liabilities using relevant primary human immune cells during early drug development is critical for the safety of drugs in the clinic and remains an unmet need.

Drug-induced immunotoxicity can manifest as:

  • a suppression of the immune response; leading to decreased resistance to infection or tumor cells
  • an escalated immune response; which can magnify autoimmune disease or trigger hypersensitivity reactions

Predictive immunotoxicology is challenging due to the complexity of the human immune system and differences in individual characteristics such as genetic variations (HLA alleles and SNPs) and immunoregulatory factors that can influence the immune response. No current animal model of drug hypersensitivity recapitulates the human immune system. In addition, recent studies suggesting that an individual’s immunoregulatory factors and, by extension, susceptibility to drug hypersensitivity can vary during their lifetime represents a further challenge to be overcome.

Peripheral blood mononuclear cells (PBMC) are an invaluable tool for the pursuit of toxicology assessment in early drug discovery and development. These cells (consisting of lymphocytes, monocytes and dendritic cells in humans) are often influenced by drugs and chemicals, resulting in adverse effects targeting multiple organs.

Using a screen of 27 reference compounds (including drugs known to stimulate hypersensitivity reactions) and PBMC isolated from 6 healthy donors, Cyprotex has developed a high-throughput early screening assay to investigate the cytotoxic potential of candidate drugs by monitoring cellular ATP depletion and LDH release. Furthermore, by using our recently established PBMC biobank, there is an opportunity to study donor dependent PBMC cytotoxicity, offering further, detailed insight into how an individual donor might respond to the candidate drug being studied.

To find out more about the work behind the assay, download the poster here.

And to read more about our PBMC cytotoxicity service, click here.

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