Current and Future Approaches for Monitoring Responses to Anti-complement Therapeutics

Abstract

Aberrations in complement system functions have been identified as either direct or indirect pathophysiological mechanisms in many diseases and pathological conditions, such as infections, autoimmune diseases, inflammation, malignancies, and allogeneic transplantation. Currently available techniques to study complement include quantification of (a) individual complement components, (b) complement activation products, and (c) molecular mechanisms/function. An emerging area of major interest in translational studies aims to study and monitor patients on complement regulatory drugs for efficacy as well as adverse events. This area is progressing rapidly with several anti-complement therapeutics under development, in clinical trials, or already in clinical use. In this review, we summarized the appropriate indications, techniques, and interpretations of basic complement analyses, exemplified by a number of clinical disorders.

Keywords: CV%; clinical trial; functional assays; immunoassays; laboratory investigation.

Figure 1

Activation and regulation of the complement system. Activation occurs via the lectin pathway (LP), the classical pathway (CP), and the alternative pathway (AP). Regulation occurs at distinct points. Level 1: inhibition of proteases generated by the LP and AP; level 2: control of the C3 convertases; level 3: control of the C5 convertases; level 4: control of the formation of the C5b-9 complex of the terminal pathway (TP).

Figure 2

Schematic overview of the flow of events in the process for analysis of clinical patient samples. Reliable analysis of samples requires the control of pre-analytical handling of and choice and validation of appropriate analytical techniques, Detailed information is given in the section “Pre-analytical handling and methodological considerations”.