The approval in the US and Europe of Eculizumab in 2007 marked a change in complement therapeutics, and with it the landscape for complement testing in the clinical immunology laboratory changed. The change had begun even before that when C1-Inhibitor preparations were approved in the 1980s in Europe. There are now two classes of approved drugs that may impact the immunology laboratory, with two dozen more with novel modalities and potential indications that are in various stages of development. Every pathway and about every component of complement has been targeted by these drug development programs, and the modalities of the drugs in development are diverse. These developments will likely result in more laboratories offering more complement testing, so this review looks forward to some of those possible changes in testing.

Introduction

Complement was recognized for its important role in innate humoral immunity as early as the 1900s, but only in the recent past have we seen the advent of drugs targeting complement [1]. This development was propelled by recognition of the fact that the roles and effects of complement extend far beyond just infection control [2, 3]. There are currently two points in the complement system that are targeted by approved pharmaceuticals, but there are therapeutics in development that target just about every component of complement [4]. The modalities and modes of action are almost as varied as the components targeted [5, 6]. This adds to the complexity of the requests coming to the clinical immunology laboratory around complement testing. Running a C3 and C4 level, and possibly a version of the total complement function assay, may have been sufficient in the past, but as these new therapeutics evolve immunology laboratories face increased calls to do a greater variety of complement testing with accelerated delivery deadlines. The first therapeutic specifically targeting the complement pathway was Eculizumab (trade name Soliris®) which was approved both in the US and in Europe in 2007 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) [7]. Before that C1-Inhibitor (C1-INH) was utilized in Europe and other countries as early as 1980s; the HIV epidemic slowed approval in the US. The FDA approved Soliris® then approved Berinert® and Cinryze® in 2008, with approval for Kalbitor® coming in 2009, all for Hereditary Angioedema (HAE) treatment [8-10]. Soliris® was approved in 2011 for a second indication, atypical Hemolytic Uremic Syndrome (aHUS). That same year Firazyr® was approved for HAE; Ruconest® followed in 2014.[11]. Most recently Soliris® was approved for Myasthenia Gravis (MG) and another HAE drug HAEGARDA® was approved in 2017 [12, 13]. These seven approved drugs fall into two areas of inhibition: the HAE drugs’ impact is early in the classical and lectin pathways, and Soliris® inhibition is in the terminal pathway. At this point almost every component of the complement cascade is being targeted [6]. This discussion is not intended to be a review of the specific therapeutics in development, as that has been done elsewhere [6, 14, 15]. Instead, we will focus on where in the cascade therapeutics are being targeted and how that is likely to affect clinical immunology laboratory testing. This paper will step through the pathways of complement individually, alongside the current and likely future testing requirements. As we discuss each pathway we will delve into how laboratory testing in complement will be impacted not only by the important step of diagnostic testing, but by the need for testing to follow compliance, to quantify drug levels and to verify the efficacy of the level of drug administration.