What’s lurking in that high background?
Annually, the European pharma industry invests more than € 35 000 million to identify and develop new drugs, about 22% of which is spent on screening assays and toxicity testing. Of the 5000 compounds that enter pre-clinical testing, only five make it to the clinical phase. An important contributing factor is the lack of suitable models and assays to evaluate the safety of drug candidates. The infusion of biological drugs may cause serious unwanted reactions such as cytokine release syndrome (CRS) in humans. The TGN1412 disaster in London 2006 bore witness to the urgent need for predictive human-based in vitro assays to assess safety. The need for more physiologically relevant assays was further fortified in a cytokine release workshop by regulatory authorities where the topics presented encompassed a regulatory perspective on cytokine release and the translatability of preclinical cytokine data to the clinic.
Immuneed’s blood loop, is a model of fresh, circulating human blood that offers unmatched quality in predicting cytokine release. Commonly used assays often fail in predicting responses to substances known to cause severe cytokine release in humans. The loop can not only detect that a substance has a high risk of inducing cytokine release but also capture moderate to low responses. We demonstrate this in a comparative study:
We performed a direct comparison of cytokine release in the blood loop with a PBMC assay (with surface-coated antibodies) in response to antibodies associated with either low (Natalizumab and Cetuximab) or high (alemtuzumab and anti-CD28) risk of inducing cytokine release in patients. The background in the loop system is lower and antibodies with a high risk of inducing cytokine release induce equal or even higher cytokine release in the loop system as compared to the PBMC assay. Since the separation between background and the positive response is much greater in the loop, the signal-to-noise ratio is superior to that of the PBMC assay. The lower background and a greater signal-to-noise ratio allow the detection of low-to-moderate responses in addition to super agonistic responses such as anti-CD28. In addition, the variation between donors is lower, which means that fewer donors are needed to run a predictive safety assessment in the loop system.
Figure 1. Cytokine release in the loop system compared to an alternative PBMC assay (with surface coated Abs). With the high background of cytokine release, PBMC assays display a poor sensitivity for scoring cytokine release compared to the blood loop assay.
To find out more about how we help companies assess the safety of drug candidates, you can reach us here.
- To read more about the cytokine release workshop, click here.