REVIEW

CURRENT
OPINION Breaking down the complement system: a review
and update on novel therapies
Yuvaram N.V. Reddy a, Andrew M. Siedlecki b, and Jean M. Francis a

Purpose of review
The complement system represents one of the more primitive forms of innate immunity. It has increasingly
been found to contribute to pathologies in the native and transplanted kidney. We provide a concise
review of the physiology of the complement cascade, and discuss current and upcoming complement-based
therapies.
Recent findings
Current agents in clinical use either bind to complement components directly or prevent complement from
binding to antibodies affixed to the endothelial surface. These include C1 esterase inhibitors, anti-C5
mAbs, anti-CD20 mAbs, and proteasome inhibitors. Treatment continues to show efficacy in the atypical
hemolytic uremic syndrome and antibody-mediated rejection. Promising agents not currently available
include CCX168, TP10, AMY-101, factor D inhibitors, coversin, and compstatin. Several new trials are
targeting complement inhibition to treat antineutrophilic cystoplasmic antibody (ANCA)-associated
vasculitis, C3 glomerulopathy, thrombotic microangiopathy, and IgA nephropathy. New agents for the
treatment of the atypical hemolytic uremic syndrome are also in development.
Summary
Complement-based therapies are being considered for targeted therapy in the atypical hemolytic uremic
syndrome and antibody-mediated rejection, C3 glomerulopathy, and ANCA-associated vasculitis. A few
agents are currently in use as orphan drugs. A number of other drugs are in clinical trials and, overall, are
showing promising preliminary results.
Keywords
antibody mediated rejection, atypical hemolytic uremic syndrome, C3 glomerulopathy, complement

INTRODUCTION OVERVIEW OF THE COMPLEMENT

The complement system represents a complex num- SYSTEM
ber of proteins that provide innate immunity and There are a number of excellent reviews that
&&
modulate acquired immunity [1 ,24]. Its main describe the complement system in great detail
&&
function is to facilitate the clearance of immune [1 ]. We aim to provide a simple, concise overview
complexes and debris from injured cells [5] and to of the complement cascade. The complement
defend against invading pathogens [6]. Deficiencies system consists of three pathways the classic
or mutations within the complement regulatory pathway, the lectin pathway (also known as the
proteins have been linked to several diseases, rang- mannose binding lectin pathway), and the alterna-
ing from relatively uncommon diseases such as the tive pathway.
atypical hemolytic uremic syndrome (aHUS) and C3
glomerulopathy (C3G), to common diseases such as
&
schizophrenia [7], obstructive sleep apnea [8 ] and a
Department of Medicine, Division of Nephrology, Boston Medical Center
ankylosing spondylitis [9]. Through a better under-
and bDepartment of Medicine, Division of Nephrology, Brigham and
standing of these diseases, complement pathways Women Hospital, Boston, Massachusetts, USA
are being targeted to improve patient outcomes. Correspondence to Jean M. Francis, MD, Department of Medicine,
&&
[911,12 ] This study serves to provide a concise Division of Nephrology, Boston Medical Center, 650 Albany St #
review of the basic functioning of the complement 605, Boston, MA 02118, USA.
system as well as an update on current and prom- Tel: +1 617 414 5282; e-mail: Jean.francis@bmc.org
ising therapies for disorders associated with dysre- Curr Opin Nephrol Hypertens 2017, 26:123128
gulation of the complement system. DOI:10.1097/MNH.0000000000000305

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Clinical nephrology

as the alternative pathways C3 convertase. As a

KEY POINTS result of C3 convertase formation, C3b production
 The complement cascade is activated by three is amplified. The alternative pathway can be
pathways, the classic, lectin, and alternative pathway. initiated and regulated by a protein called proper-
Mechanistically, it is also classified into three arms, the din. Factor D is the rate-limiting step in the alterna-
initiation, amplification, and termination arms. tive pathway, and, as a result, is considered a
potential target for the treatment of paroxysmal
 The complement cascade plays a role in innate and
acquired immunity. As a result, strategically designed nocturnal hemoglobinuria (PNH) and aHUS.
drugs that act on various sites in the complement Termination arm (Fig. 1d): C3b formed in all
cascade can have varying beneficial results, allowing three pathways binds to C3 convertase (C4bC2a) of
for targeted immune modification. the classic or lectin pathway to form C5 convertase
(C4bC2aC3b). It also binds to the alternative path-
 Current complement agents in use include eculizumab,
anti-MASP antibody, and C1 esterase inhibitors. ways C3 convertase (C3bBb) to form (C3bC3bBb)
the alternative pathways C5 convertase [13]. This
 Upcoming and promising agents include CCX168, converts C5 to C5a (an anaphylatoxin) and C5b.
TP10, AMY-101, ACH-4471, coversin, and compstatin. C5b binds to C6C9 to form the membrane attack
 Complement-based therapy has potential benefits for complex (MAC) that promotes lysis of microbes or
diseases such as the atypical hemolytic uremic cell injury in cases of complement regulatory
syndrome, paroxysmal nocturnal hemoglobinuria, proteins deficiency as in aHUS. MAC is currently
ischemiareperfusion injury; acute and chronic viewed as a proinflammatory agent that can initiate
antibody-mediated rejection; C3G (including dense endothelial cell injury and death. Of note, MAC is
deposit disease and C3 glomerulonephritis), IgA
regulated by surface receptors, which include comp-
nephropathy, and ANCA-associated vasculitis.
lement receptor type 1 (CR1 or CD35), membrane
cofactor protein (MCP or CD46), decay accelerator
factor (DAF or CD55), and CD59. These regulatory
As it relates to therapeutics, the complement mechanisms have been found to have relevance in
cascade can be broken down into three arms: diseases caused by excessive, unregulated comp-
initiation, amplification, and termination. They lement activation, such as dense deposit disease,
are represented in Fig. 1a, and are described below: PNH, and aHUS [12 ].
&&

Initiation arm (Fig. 1b): the complement path- A variety of agents that target the classic,
way can be initiated via three possible pathways alternative, and terminal complement cascades
the alternative, classic, and lectin pathway. The are currently being used in the clinical setting (Table
classic pathway is activated by antigenantibody 1).
immune complexes (bound to C1q), whereas, the
lectin pathway is activated by microbial carbo-
hydrates [bound to mannose binding lectins COMPLEMENT-BASED THERAPIES IN
(MBL) and ficolins]. Activation of either pathway CLINICAL USE
results in the splitting of C2 and C4 to form the C1-INH is a protease inhibitor belonging to the
classic or lectin pathway C3 convertase (also called serpin superfamily. Its main function is the inhi-
C4bC2a). C4bC2a formation is regulated by the C1 bition of the complement system to prevent spon-
esterase inhibitor (C1-INH), which is a target for taneous activation. This protease inhibitor regulates
therapy in hereditary angioedema. The lectin path- the initiation arm of the classic and lectin pathways
way is also specifically regulated by MBL-associated by binding to C1r and C1s of the classic pathway,
serine proteases (MASP1, MASP2, and MASP3) that and MASP1, and MASP2 of the lectin pathway,
cleave C4 and C2. MASP is a target of therapy for thereby blocking the initiation phase of these two
thrombotic microangiopathy. pathways (Fig. 1b). C1-INH indirectly affects the
Amplification arm (Fig. 1c): The alternative alternative pathway, and allows for maintained
pathway is constitutively active, and its activity is MAC activity and bacteriolysis. C1-INH agents are
amplified by the activation of the alternative or currently approved for use in hereditary angioe-
lectin pathways. The alternative pathway can medi- dema, a defect most commonly caused by a
ate the amplification arm of the complement cas- deficiency in C1-INH [14]. There are no recent stud-
cade. C3 convertase formed by the initiation arm, ies utilizing C1-INH for hypocomplementemic urti-
facilitates the conversion of C3 to C3a (an anaphy- carial vasculitis with renal involvement, but this
latoxin) and C3b. C3b in combination with factor D, therapy would have theoretical benefit. Three
converts factor B to Bb. Factor Bb binds to C3b, plasma-derived C1-INH agents are available in
resulting in formation of C3bBb, which functions Europe and in the United States, including Berinert

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 Breaking down the complement system Reddy et al.

FIGURE 1. (a): Overview of the complement cascade. (b): Simplified view of the initiation arm of the complement cascade.
(c): Simplified view of the amplification arm of the complement cascade. (d): Simplified view of the termination arm of the
complement cascade.

(Company CSL Behring, Pennsylvania, USA), Cone- considered for use in patients at relatively higher
stat alfa (Ruconest, Salix Pharmaceuticals, Inc.), and risk for severe early or chronic antibody-mediated
Cinryze (Company Shire PLC). Endogenous C1-INH rejection. Thus far, early human studies have
is believed to ameliorate acute and chronic anti- suggested a clinical benefit for these indications
body-mediated rejection, and has been shown to [16,17]. Although it is recognized that C1-INH inter-
be effective in animal studies and some preliminary acts with the fibrinogen and kininogen cascades in
human studies in alleviating antibody-mediated addition to complement cascades, safety studies
rejection [15]. Theoretically, C1-INH could be have demonstrated no unique toxicity or major

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Clinical nephrology

Table 1. List of complement based therapies for renal disorders

Drug Class Name Current use Potential use

C1 esterase inhibitor Berinert, conestat Alfa, Cinryze Acute and chronic graft injury
(Transplantation)
MASP inhibitor OMS721 TMA aHUS
IGA nephropathy
Anti-C5 antibody Eculizumab PNH Delayed AMR
AHUS Transplant associated TMA
Idiopathic Membranous GN
C5aR antibody CCX168 ANCA vasculitis
aHUS [with congenital complement
abnormality]
C3 inhibiting peptide AMY 101 PNH
compstatin
C3 soluble complement receptor TP 10 C3 Glomerulonephritis
DDD
C5 inhibitor Coversin PNH
Factor D inhibitor ACH-4471 PNH

aHUS, atypical hemolytic uremic syndrome; AMR, antibody mediated rejection; ANCA, antineutrophil cytoplasmic antibody; DDD, dense deposit disease; PNH,
paroxysmal nocturnal hemoglobinuria; TMA, thrombotic microangiopathy.

adverse effects to using plasma derived C1-INH. As complex formation and acquired immune response.
C1-INH agents affect the classic and lectin path- An anti-MASP antibody (OMS721) is currently being
ways, they are considered nonselective and impair tested in clinical trials for use in thrombotic micro-
host immune regulation to a greater effect than angiopathy, aHUS (Clinical Trial Registration No.
other agents listed below. NCT02222545) and IgA nephropathy (Clinical Trial
Eculizumab (Soliris, Alexion Pharmaceuticals, Registration No. NCT02682407).
Inc) is a humanized anti-C5 antibody that acts to Coversin, a lipocalin protein, binds to a unique
inhibit the termination arm of the complement C5 moiety, and, inhibits both the release of C5a,
cascade (Fig. 1d), preventing MAC formation and and, and MAC formation (Fig. 1d). As it binds to a
complement-mediated inflammation and cell different C5 moiety than eculizumab, coversin may
injury. This agent was originally approved in the offer an alternative to patients with C5 molecular
United States for use in PNH, and is now approved polymorphism or patients with complement medi-
for use in aHUS (as of December 2011). In patients ated HUS recalcitrant to eculizumab. It is being
with solid organ transplant or stem cell transplant- tested as subcutaneous injection form. It is being
associated thrombotic microangiopathy refractory considered for use in PNH, aHUS, and the Guillain
to discontinuation of calcineurin inhibitors and Barre syndrome [21]. Phase 1b trials in healthy
plasma exchange, eculizumab has been shown to volunteers are ongoing, and phase 2 trials for PNH
improve 1-year survival [18]. Studies have also are expected to begin in late 2016.
suggested that eculizumab may stabilize kidney CCX168 is a C5a receptor (C5aR) inhibitor,
function in kidney transplant recipients by reducing which was designed to block C5a (anaphylatoxin)
the rate of acute antibody-mediated rejection, with mediated inflammation in the termination arm
persistent donor-specific antibodies [1820]. It is (Fig. 1d). Thus far, it has been studied for antineu-
therefore being considered for use in chronic anti- trophilic cystoplasmic antibody (ANCA)-associated
body-mediated rejection, as well as transplant vasculitis, and aHUS [20]. Enrollment for two phase
associated thrombotic microangiopathy. 2 trials, C5aR inhibitor on leukocytes exploratory
ANCA-associated renal vasculitis (CLEAR) and
clinical ANCA vasculitis safety and efficacy study
COMPLEMENT-BASED THERAPIES UNDER of inhibitor of C5aR (CLASSIC) is near completion
INVESTIGATION (Table 2). These trials have been designed with the
The MBL-associated serine protease regulates the primary intent of eliminating or reducing high-dose
initiation arm of the lectin pathway (Fig. 1b). Unlike corticosteroid use without compromising efficacy or
C1-INH, MASP does not involve the classic pathway, safety, while evaluating disease activity using the
and, allows for maintenance of antigenantibody Birmingham Vasculitis Activity Score [22].

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 Breaking down the complement system Reddy et al.

Table 2. List of complement based therapies for renal and nonrenal disorders

Drug Class Name Indications under consideration

Anti-C5 aptamer Avacincaptad Macular degeneration

B-cell-activating factor antagonist Blisibimod Systemic lupus Erythematosus
B-cell-activating factor antibody Belimumab Systemic lupus Erythematosus
C1 esterase inhibitor Cinryze Hereditary angioedema; Acute and chronic graft injury
(Transplantation)
C1 esterase inhibitor Conestat alfa Hereditary angioedema; acute and chronic graft injury
(Transplantation)
C1 esterase inhibitor Berinert Hereditary angioedema; acute and chronic graft injury
(Transplantation)
C5aR inhibitor CCX168 ANCA vasculitis; atypical Hemolytic uremic syndrome (with
congenital complement abnormality)
C5-inhibitor (fusion protein) Coversin Paroxysmal nocturnal hemoglobinuria
CTLA-4 fusion protein Abatacept Granulomatosis with vasculitis
CTLA-4 fusion protein Belatacept Antibody-mediated transplant rejection
C5 antibody Eculizumab atypical hemolytic uremic syndrome; paroxysmal nocturnal
hemoglobinuria; Delayed antibody-mediated rejection;
transplant associated-thrombotic microangiopathy; -
idiopathic membranous glomerulonephritis
Glycolipid GD2 antibody Dinutuximab b Neuroblastoma
MASP antibody OMS721 thrombotic microangiopathy; atypical hemolytic uremic
Syndrome; IgA nephropathy
Monoclonal CD20 antibody Ofatumumab Chronic lymphocytic leukemia
Properdin inhibitor CLG561 Macular degeneration
Proteasome inhibitor Ixazomib Multiple myeloma
RNAi to Hep B cDNA ARC-521 Chronic hepatitis B
C3 soluble complement receptor TP10 C3 Glomerulonephritis; dense deposit disease
C3 inhibiting peptide AMY 101 Paroxysmal nocturnal Hemoglobinuria
Compstatin
Sphingosine-1-phosphate-1 receptor antagonist MT-1303 Multiple sclerosis
Tumor necrosis factor a antibody Certolizumab Rheumatoid arthritis
Tyrosine kinase inhibitor Ibrutinib Chronic lymphocytic leukemia
Factor D inhibitor ACH-4471 Paroxysmal nocturnal hemoglobinuria

C3G defines a group of renal disorders charac- also being considered for ischemiareperfusion
terized by pronounced C3 deposition in the kidneys injury [26,27], as well as for the treatment of C3G.
in the absence of deposited immunoglobulins [23]. Cp40 may have role in xenotransplantation to
It is subclassified into dense deposit disease and C3 reduce acute xenogeneic reactions [28].
glomerulonephritis. These patients have an overall Factor D inhibitors are agents that mitigate the
poor prognosis, and medical management is cur- complement-mediated amplification step of the
rently supportive with blood pressure control and alternative pathway (Fig. 1c). ACH-4471, one such
immunosuppression [24,25]. TP10 is a C3 conver- agent, is being considered for PNH and aHUS. This
tase inhibitor that acts as a soluble complement agent can be given orally, and, would therefore have
receptor, blocking the amplification arm of the a delivery advantage over intravenously infused
complement cascade (Fig. 1c). This agent is being agents if future trials are successful [29]. At present,
considered as a candidate for C3G. A phase 1 trial is ACH-4471 is in phase 1 clinical trials outside of the
currently underway and, is expected to be finished United States.
in December 2016. Avacincaptad is an anti-C5 aptamer. This drug
C3 inhibitors, AMY-101, and Cp40, are nearing design is in contrast to mAbs targeting the same
the stage of clinical trial investigation but remain in complement component. Based on public infor-
the preclinical phase. AMY 101 is a new class of mation available, it is unclear if this agent is a
compstatin derivatives, a group of agents that are protein or nucleotide aptamer. Phase 2/3 trials are

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Clinical nephrology

4. Koscielska-Kasprzak K, Bartoszek D, Myszka M, et al. The complement

underway in the United States to assess for efficacy cascade and renal disease. Arch Immunol Ther Exp (Warsz) 2014;
in age-related macular degeneration (Clinical Trial 62:4757.
5. Noris M, Remuzzi G. Glomerular diseases dependent on complement activa-
Registration No. NCT02686658). tion, including atypical hemolytic uremic syndrome, membranoproliferative
Table 2 comprises a more representative list of glomerulonephritis, and C3 glomerulopathy: Core Curriculum 2015. Am J
Kidney Dis 2015; 66:359375.
promising agents, including complement-based 6. Noris M, Remuzzi G. Overview of complement activation and regulation.
therapies that might have a role in nonrenal Semin Nephrol 2013; 33:479492.
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8. Emin M, Wang G, Castagna F, et al. Increased internalization of complement
& inhibitor CD59 may contribute to endothelial inflammation in obstructive sleep
apnea. Sci Transl Med 2016; 8:320ra1.
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immune and nonimmune-mediated disorders. It spondylitis progression. Sci Rep 2016; 6:34643.
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bition at select sites results in varying consequences. && apeutics to rare diseases. Clin Immunol 2015; 161:225240.
Clear and extensive review on pathophysiology of complement disorders with
Current therapeutic agents, such as eculizumab, discussion on therapeutic agents in trial and practice for renal and other fields.
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