When is complement activation a risk?

Why is a key aspect of the body’s immune system almost systematically overlooked in preclinical assays?

Preclinical testing is vital to ensure the safety of clinical trials. So why is a key aspect of the body’s immune system almost systematically overlooked in preclinical assays? The complement system comprises upwards of 40 blood proteins synthesized by the liver. When activated, these small proteins start a cascading immune response, stimulating phagocyte action, inflammation and membrane attack complex. Complement activation can be a cause of infusion reactions, including hypersensitivity reactions involving complement-dependent cytotoxicity (CDC). CDC is an important and powerful aspect of the innate immune system. Yet the focus in preclinical trials is almost entirely on antibody-dependent cell-mediated cytotoxicity (ADCC). Because antibodies can be modified to prevent CDC, many assume that evaluating complement activation is unnecessary. But there’s a significant flaw in that reasoning.

Three pathways to complement activation

Complement activation can’t be switched off entirely. The complement system can be activated through three distinct mechanisms: the classical pathway, the alternative pathway and the lectin pathway. While antibody mutations can prevent complement activation via the classical pathway, the alternative pathway remains a potential danger.  For that reason, preclinical trials should always look for complement activation, even if no activation is expected. A clinical CRO that Immuneed partners with, Clinical Trial Consultants, has shared firsthand experience. “During clinical trials, we have observed immunotoxicity related to the complement pathway,” says Chief Science Officer Bengt Dahlström. “A safety evaluation including the complement should always be included in the preclinical program to mitigate risks and unexpected adverse events during the trial.”

Safety means looking at all factors

Unfortunately, many pharmaceutical developers don’t include complement evaluation in preclinical trials. Whether they are unaware of it or choose to ignore it for reasons of expediency, they put clinical trial subjects and reputation at risk by not taking the alternative pathway into account. Traditionally, separate assays have been needed for ADCC and CDC, which may explain the frequency of the shortcut. Today, however, ADCC and CDC can be evaluated in the same assay. Immuneed’s platform with fresh, circulating human blood is unique in having an intact complement system. Not only can it identify complement activation via the alternative pathway, it can also assess ADCC and CDC simultaneously. At times, these two mechanisms block or complement each other, which means there’s a functional advantage to studying them together. Would you like to know more about evaluating complement activation or the comprehensive possibilities of Immuneed’s platform? We’d be happy to discuss both. Get in touch with us here.