Complement Activation & Inhibition

How does your drug interact with the human complement system?

Complement activation or inhibition could influence your drug’s function, whether you anticipate it or not. The human complement system comprises upwards of 40 proteins. Although small, these proteins can trigger a massive immune response, starting a cascading reaction that stimulates phagocyte activation, inflammation, and membrane attack complex. In a clinical trial, they can be the source of significant infusion reactions, such as hypersensitivity reactions caused by the complement system.  These include reactions based on complement-dependent cytotoxicity (CDC), which can be prevented through antibody modification. But they also include reactions based on antibody-dependent cell-mediated cytotoxicity (ADCC), which is frequently overlooked. The latter can occur via the alternative pathway, which remains active even when the classical pathway has been blocked. You get the complete picture by including complement evaluation in your preclinical testing.

Why complement must be assessed in fresh human blood

Tests based on plasma from rabbits or other animals are limited in what they can reveal. Likewise, in vitro testing in animals – including apes – is an imperfect analogy for a human environment. Immunee’ds platform ID.Flow, is based on fresh, circulating human blood and is unique in having an intact, and active complement system.

The Figure above shows a study of complement activation in ID.Flow.  The figure shows the activation of complement subunits C3a and C5a as assessed by ELISA in fresh human blood from five healthy donors. The donor responses are compared to PBS (vehicle) and different monoclonal antibody controls in ID.Flow as compared to blood collected before addition to ID.Flow (zero sample).