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

Maedeh Mohebnasab,Kristina N Ekdahl,Oskar Eriksson,Camilla Mohlin,Kerstin Sandholm,Bo Nilsson,Barbro Persson,Markus Huber-Lang,Brendan J Keating

doi:10.3389/fimmu.2019.02539

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.

Highlights

Physiological and Therapeutic Regulation of Complement ActivationThe complement system consists of more than 50 soluble and membrane-bound proteins that function in both innate and adaptive immunity
The underlying mechanisms include [1] increased and persistent activation, such as that resulting from the presence of soluble or solid-phase immune complexes as in systemic lupus erythematosus (SLE), myasthenia gravis, and related autoimmune disorders; [2] altered expression or function of various complement regulators as in paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, and C3 glomerulopathies (C3G); or [3] a combination of the two
It has become evident that there is a pressing need to improve monitoring of the complement status in patients receiving treatment with these drugs; a need that is only expected to increase in the future given the extensive list of complementtargeting drugs that are in clinical trials

Summary

INTRODUCTION

The complement system consists of more than 50 soluble and membrane-bound proteins that function in both innate and adaptive immunity. The third factor I-mediated cleavage splits the molecule into the target-bound C4d and C3d,g (a ligand for CR2 or CD21) fragments and C4c/C3c, which is released from the activating surface At this level, there are a number of regulators that protect autologous cell surfaces against complement attack. There are a number of regulators that protect autologous cell surfaces against complement attack These include membrane-bound molecules, such as CR1, decay acceleration factor (DAF; CD55), and membrane cofactor protein (MCP; CD46), all of which disrupt the C3 convertases by different mechanisms [1]. Alnylam Pharmaceuticals has developed a C5-directed RNAi therapeutic that is liver-targeted through GalNAc conjugation and silences intrahepatic expression of C5 [5, 7] This strategy leads to a systemic reduction in C5 levels and terminal pathway activity, and is currently being trialed as a therapy for PNH and aHUS. While some antisense therapies are directed systemically, this strategy offers an opportunity to target complement factors in a specific tissue or at the site of disease through delivery systems, such as antibodies

ANALYTICAL METHODS

Findings

DISCUSSION