Expert Opinion on Drug Discovery

ISSN: 1746-0441 (Print) 1746-045X (Online) Journal homepage: http://www.tandfonline.com/loi/iedc20

Evolution of compstatin family as therapeutic

complement inhibitors

Yijun Huang

To cite this article: Yijun Huang (2018): Evolution of compstatin family as therapeutic complement
inhibitors, Expert Opinion on Drug Discovery, DOI: 10.1080/17460441.2018.1437139

To link to this article: https://doi.org/10.1080/17460441.2018.1437139

Published online: 05 Feb 2018.

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EXPERT OPINION ON DRUG DISCOVERY, 2018
https://doi.org/10.1080/17460441.2018.1437139

REVIEW

Evolution of compstatin family as therapeutic complement inhibitors

Yijun Huang
WuXi AppTec Inc., Philadelphia, PA, USA

ABSTRACT ARTICLE HISTORY

Introduction: Therapeutic modulation of complement activation is considered as a promising approach Received 20 November 2017
for the treatment of host tissue damage in several inflammatory and autoimmune diseases. Accepted 2 February 2018
Complement component protein C3 is a particularly attractive drug target for complement inhibitors, KEYWORDS
due to its central role in three pathways of complement activation cascade. Complement inhibitor;
Areas covered: The author provides a comprehensive review on compstatin family peptides which compstatin; immunology;
have been discovered and optimized as potent and selective C3 inhibitors via a combination of structure–activity
chemical, biophysical and computational approaches. New generations of the compstatin family with relationship; peptide drug;
improved potency and therapeutic properties have been developed in recent years. Over two decades, drug development
compstatin demonstrated therapeutic potential as a first-of-its-kind complement inhibitor in a series of
disease models, with encouraging efforts in clinical trials.
Expert opinion: Compstatin holds promise for new therapeutic implications in blocking the effect of
the complement cascade in a variety of disease conditions. The development of cost-effective treat-
ment options with suitable dosing route and schedule will be critical for patients with complement
mediated chronic diseases.

1. Introduction in the amplification phase of the complement cascade [13]. C3

convertase can cleave C3 molecules into C3a and C3b, which
Human complement system is a cascading network involving
is deposited on the microbe surface and recognized by com-
over 30 plasma and cell surface proteins that play crucial roles
plement receptors on phagocytic cells, thus results in inflam-
in immune defense to recognize and remove pathogens and
mation and elimination of self and non-self targets. The
infected cells [1]. Complement activation is tightly controlled
inhibition of C3 has long been conceived a promising ther-
in normal physiology, however, inappropriate or uncontrolled
apeutic strategy for patients to prevent the activation of the
activation of complement contributes to the damages of host
complement pathway [14]. Inhibitors targeting C3, a critical
cells in many inflammatory diseases and disorders [2,3]. The
convergence point of three activation pathways, would offer
inhibition of complement activation has been found to be
advantages over eculizumab, which only blocks the terminal
prominent in the therapeutic development arena for the treat-
complement cascade [15]. Since a peptide C3 inhibitor named
ment of autoimmune and inflammatory diseases [4–6].
compstatin discovered in 1996, it has been a remarkable
Eculizumab, a monoclonal antibody directed against the com-
journey to develop complement therapeutics that can specifi-
plement protein C5, is a first-in-class drug approved by FDA
cally bind to C3 and inhibit complement activation [16]. This
for the treatment of a rare form of hemolytic anemia called
paper highlights the milestones for the evolution of compsta-
paroxysmal nocturnal hemoglobinuria (PNH) in 2007 [7]. In
tin family and investigations of compstatins as therapeutic
2011, eculizumab was approved for the patients with atypical
complement inhibitors.
hemolytic-uremic syndrome (aHUS) to inhibit complement-
mediated thrombotic microangiopathy [8,9]. Due to wide ther-
apeutic implications of complement inhibition in many dis- 2. Compstatin: discovery and mechanism of action
ease models, there is an emerging need to develop
The three-dimensional structure of the central complement
complement inhibitors for the treatment of complement-
component C3 was resolved by Gros and coworkers in 2005
mediated diseases, which affect millions of patients with
[17,18]. The native C3 (1,641 amino acid residues) consists of
unmet medical needs [10,11].
13 domains formed by α and β chains, which are linked by a
Complement component protein C3, the most abundant
disulfide bond and non-covalent interactions. The core of C3
protein of the complement system (0.75–1.35 mg/mL in
consists of eight homologous macroglobulin domains
plasma), occupies an outstanding position in complement
involved in host defense mechanisms. C3 is critical to label
activation cascade [12]. C3 activation is central to three com-
cells and cellular debris for immune clearance initiated by the
plement pathways (the classical pathway, the alternative path-
covalent attachment of a reactive thioester. In thioester-con-
way, and the mannose-binding lectin pathway), and involved
taining domain, an internal cycloglutamyl cysteine thioester is

CONTACT Yijun Huang huang@alumni.pitt.edu WuXi AppTec Inc., 4701 League Island Boulevard, Philadelphia, PA 19112, USA
© 2018 Informa UK Limited, trading as Taylor & Francis Group
2 Y. HUANG

interfere with complement regulation proteins or involve the

Article highlights destabilization of the C3 convertase [25].
● As a first-of-its-kind complement inhibitor, compstatin has unique
As a complement-based anti-inflammatory therapeutics,
mechnism of action to modulate complement activation. compstatin is one of the few clinically evaluated protein-pro-
● Integrated approaches were developed for the structure–activity tein interaction inhibitors. A crystal structure of C3c–compsta-
based lead optimization of compstatin analogs.
● Tremendous efforts have been made to investigate compstatin in a
tin complex reveals that compstatin sterically blocks the
wide variety of disease models in vitro and in vivo. access of C3 to the convertase, thus results in the inhibition
● New generations of compstatin were developed with improved of complement activation [26]. The binding site of a represen-
pharmacodynamic and pharmacokinetic properties.
● Compstatin family has been investigatedas therapeutic complement
tative example of compstatin (I[CVWQDWGAHRC]T) is formed
inhibitors in several clinical trials. by a shallow groove between macroglobulin (MG) domains 4
● There is a need to promote industry and academia collaboration to and 5 of the β-chain of C3c (Figure 1a). Compstatin forms an
accelerate complement based drug development process, particularly
on developing new therapies to treat rare diseases.
extensive hydrogen bond network with the receptor C3c
(KD = 0.39 µM). The main-chain nitrogen of Ile1 forms a
This box summarizes key points contained in the article. hydrogen bond with the side-chain residue of Asn390; the
main-chain nitrogen of Trp4 forms a hydrogen bond with
the main-chain oxygen of Gly345; the main-chain oxygen of
Trp4 forms a hydrogen bond with the side-chain residue of
formed between Cys988 and Gln991. Upon proteolytic activa- Arg456; the side-chain residue of Gln5 forms a hydrogen bond
tion, the anaphylatoxin domain between Arg726 and Ser727 with the side-chain residue of Asp491; the side-chain residue
can be cleaved by C3 convertase to form a small fragment of Trp7 forms a hydrogen bond with the main-chain oxygen of
C3a. The large fragment C3b subsequently undergoes signifi- Met457; the main-chain nitrogen of His10 forms a hydrogen
cant conformational and positional changes, thus results in bond with the side-chain residue of Asp491. Compared with
domain re-arrangement [19,20]. The thioester is more than 85 the structure of free C3c (PDB file 2A74) [18], compstatin
Å away from the buried site in native C3, and is fully exposed binding does not affect the overall domain arrangement of
for covalent attachment to target surfaces. Surfaces covered C3c. Meanwhile, the compstatin binding site is structurally
by C3b are marked for destruction and clearance, which stable and conserved in C3, C3b and C3c, thus compstatin
results in the stimulation of the immune response. may bind C3 without affecting large structural changes. In
The inhibition at the C3 level would effectively block the contrast, compstatin shows distinct conformation after bind-
unregulated activation of the complement system to avoid ing to C3c (Figure 1b), compared with the solution conforma-
host cell damage [21–23]. Compstatin is a unique example of tion of free compstatin determined by a family of 21 low
complement inhibitor targeting C3, and there is no other energy NMR structures (PDB file 1A1P) [27]. This suggests
agents identified as C3 inhibitor to date [24]. The first member that compstatin undergoes an induced-fit conformational
of compstatin family, a peptide with a cyclic structure consist- change upon binding to the C3 surface. Nevertheless, this
ing of 13 amino acid residues, was discovered from a phage- co-crystal structure further confirms the key features of struc-
displayed random peptide library in 1996 [16]. This peptide (I ture–function relationship of compstatin analogs indicated by
[CVVQDWGHHRC]T, where Cys2 and Cys12 form a disulfide other biophysical and biochemical studies [28].
bridge) binds to C3 and C3 fragments, and was identified as
a complement inhibitor (classical pathway: IC50 = 63 µM; alter-
native pathway: IC50 = 12 µM). Since then, the compstatin
family has been expanded with hundreds of peptide analogs
3. Structure–activity relationship of compstatins
developed by Lambris’ laboratory and other researchers in this It is the first milestone that compstatin was originally discov-
field. In terms of mechanism of action, compstatin prevents ered by target-based screening as a main stream of drug
the cleavage of C3 by C3 convertase, however, does not discovery approach. A phage-displayed peptide library that

a. b.

Figure 1. (a) X-ray crystal structure of C3c–compstatin complex (Diffraction data was collected up to 2.4 Å resolution [26]. The figure was rendered by PyMOL from
PDB file 2QKI). The compstatin binding site of C3c is shown as a transparent surface, and selected amino acids which forms hydrogen bonds with compstatin are
shown as white sticks. Compstatin is shown as yellow sticks, and the hydrogen bonds between compstatin and C3c are shown in dash lines. (b) The cartoon
representation of the averaged minimized NMR structure of compstatin (grey) and compstatin in the co-crystal structure (yellow).
 EXPERT OPINION ON DRUG DISCOVERY 3

contains 2 × 108 unique clones expressing random 27-mer [30]. The β-turn segment (Gln5-Asp6-Trp7-Gly8) of compstatin
peptides was screened to isolate C3b binding peptides [16]. also forms three hydrogen bonds with the receptor, thus it is a
A peptide (I[CVVQDWGHHRC]TAGHMANLTSHASAI) was iden- determinant for the higher inhibitory activity (Figure 2).
tified as a complement inhibitor (classical pathway: Notably, the side-chain residue of Trp7 is deeply buried
IC50 = 65 µM; alternative pathway: IC50 = 19 µM). The trunca- in a hydrophobic pocket, and forms a hydrogen bond with
tions of the parent peptide led to identify its N-terminal region the main-chain oxygen of Met457. The replacement of Trp7
(marked in bold) as the functional fragment, and this 13-mer by Phe resulted in complete loss of inhibitory activity (Ac-I
cyclic peptide was later named compstatin to fulfill the pro- [CVVQDFGHHRC]T-NH2, IC50 > 400 µM) [30]. Later, compsta-
mise of developing complement inhibitors with therapeutic tin derivatives were expressed and purified from Escherichia
potential. The evolution of compstatin family represents a coli to incorporate non-natural Trp analogs (Figure 3) [33].
typical process using structure-activity relationship studies Compared with the wild-type compstatin (NH2-GI
for the development of peptide drugs. [CVWQDWGAHRC]TN-OH; IC50 = 1.2 µM), the incorporation
The biochemical and functional stability of compstatin in of 6-fuoro-tryptophan (NH2-GI[CV(6fW)QD(6fW)GAHRC]TN-
human blood was studied since it has therapeutic potential as OH; IC50 = 0.43 µM) increased the activity three-fold, while
the complement inhibitor [29]. In vitro biotransformation stu- the incorporation of 5-hydroxy-tryptophan (NH2-GI[CV(5-
dies of compstatin have shown that Ile1 was cleaved at the N OH-W)QD(5-OH-W)GAHRC]TN-OH; IC50 = 33 µM) or 7-aza-
terminus; however, proteolytic processing in blood is blocked tryptophan (NH2-GI[CV(7-aza-W)QD(7-aza-W)GAHRC]TN-
after the first amino acid residue due to the cyclic nature of OH; IC50 = 122 µM) rendered less active compstatin analogs.
compstatin. Acetylation of the amino terminus can sufficiently Similarly, the incorporation of 5-fuoro-tryptophan (Ac-I
block the removal of Ile1 from enzymatic degradation, thus [CVWQD(5fW)GAHRC]T-NH2; IC50 = 0.45 µM) increased the
increases the stability of compstatin in human blood (half-life activity three-fold relative to the wild-type compstatin (Ac-I
of 24 h at 37°C) [29]. In addition, the inhibitory activity of [CVWQDWGAHRC]T-NH2; IC50 = 1.2 µM) [34]. This further
compstatin was increased upon N-acetylation, indicating the suggests that the hydrophobic nature of Trp7 is favorable
participation of the N terminus in binding [30]. No cleavage for the interaction of compstatin with C3, thus contributes
was observed at the C terminus, since it was protected with to the inhibitory activity of compstatin.
the amide incorporated via solid-phase peptide synthesis. The disulfide bridge is essential for structural stability and
Although the introduction of D-amino acid residues is inhibitory activity of compstatin. The linear compstatin
expected to improve a peptide’s stability to proteases, comp- (ICVVQDWGHHRCT, alternative pathway: IC50 > 600 µM) com-
statin analogs incorporating D-amino acids led to dramatic pletely loses the activity [27]. Reduction and alkylation of the
loss of activity [30,31]. two cysteines also result in a loss of inhibitory activity [16]. In
Alanine scanning of compstatin (I[CVVQDWGHHRC]T, addition, the replacement of Cys2 and Cys12 with alanine
IC50 = 12 µM) was extensively investigated to identify the yielded an inactive linear analog [30]. In a recent study, a
contribution of each amino acid residue for its activity. An reduction-resistant cystathionine (Cth) bridge was introduced
alanine scan was performed within the cyclic loop of comp- as an isostere structure to replace the disulfide bond of comp-
statin analog ([CVVQDWGHHRC], the notation is aligned with statin (Figure 4) [35]. Compared with the original compstatin
compstatin sequence) [27]. This cyclic loop still retains the (Y = Z = S; IC50 = 1.9 µM), the δ-Cth-containing analog largely
activity (IC50 = 33 µM), however, studies of short constrained maintains the binding and inhibitory properties (Y = S,
peptides with any additional deletion have shown that 11- Z = CH2; IC50 = 3.1 µM), while the γ-Cth-containing analog
membered peptide between disulfide-linked Cys2 and Cys12 (Y = CH2, Z = S; IC50 > 20 µM) is nearly inactive. This suggests
constitutes a minimum structure required for optimal activity that the sulfur-to-methylene substitution on the C-terminal
[30]. The replacement of His9 by Ala yielded two-fold increase side of the original disulfide is unfavorable for the structural
in the inhibitory activity, while replacements of Val4, His10, and functional properties of compstatin. Although the δ-Cth-
and Arg11 by Ala yielded two-fold decrease in the inhibitory
activity. This suggests that Val4, His9, His10, and Arg11 do not
contribute significantly to binding with C3. However, replace-
ments of Val3, Gln5, Asp6, Trp7 and Gly8 by Ala yielded
dramatic decrease in the inhibitory activity. Furlong and cow-
orkers further studied alanine scanning of the full length
compstatin, confirming that replacements of Val4, His9 and Gly8
Arg11 by Ala resulted in minimal change in the functional Trp7
activity [31]. In contrast, replacements of Val3, Gln5, Trp7,
Gly8 and His10 by Ala yielded analogs that were inactive.
These results combined with the biophysical studies of the Asp6
compstatin structure indicate that a type I β-turn comprising
the segment Gln5-Asp6-Trp7-Gly8 is critical for its activity [32]. Gln5
However, the rest of the peptide is mainly disordered and
amenable to further optimization. The residues Gln5-Asp6-
Trp7-Gly8 substituted with Gly-Pro-Phe-Gly, which has the Figure 2. The β-turn segment (Gln5-Asp6-Trp7-Gly8) of compstatin is indispen-
propensity to form type I β-turn, yielded an inactive analog sable for high inhibitory activity.
4 Y. HUANG

Figure 3. Incorporation of unnatural amino acids at position 7 of compstatin.

Figure 4. Thioether containing analogs of compstatin (X1 = Trp, X2 = Gly,

X3 = Thr).

Figure 5. A therapeutic complement inhibitor (POT-4, AL-78898A).

containing analog is slightly weaker in terms of inhibitory

activity, the improved stability to reduction conferred by the contacts with C3, and the replacement of salvation water
thioether bond underscores the potential therapeutic benefit from a hydrophobic environment.
of disulfide-to-thioether substitution. Furthermore, N-methylation scan of the peptide backbone
Integrated computational and experimental approaches identified a compstatin analog with significantly improved
were developed for the structure-activity based lead opti- affinity and potency [39]. A backbone N-methylation scan
mization of compstatin analogs. For example, an approach showed that N-methylation of Gly8 and Thr13 produced ana-
utilized NMR-derived structural templates, combinatorial logu with slightly increased potency, however, N-methylation
selection of sequences, and prediction of fold stabilities in all other positions resulted in decreased potency. Although
for the design of compstatin variants with improved Sar8 may disturb the conformation of the original β-turn seg-
potency [36]. This study resulted in a 7-fold more active ment (Gln5-Asp6-Trp7-Gly8), it may also contribute to the
analog (I[CVYQDWGAHRC]T) with the combination of Tyr4 reduced entropic penalty by restricting rotations of local back-
and Ala9. Subsequently, several active analogs of compsta- bone bonds and making the free solution structure less flex-
tin were identified by altering its amino acid composition ible. In addition, a diverse panel of amino acid substitutions
at positions 4 and 9 [37]. The most potent analogue with 2- was investigated to replace Thr13, which lies outside the cyclic
naphthylalanine (2Nal) at position 4 and alanine at position structure of compstatin. As a consequence, one analog (Ac-I
9 (Ac-I[CV(2Nal)QDWGAHRC]T-NH2, IC50 = 0.5 µM) is 99-fold [CV(1MeW)QDW-Sar-AHRC](NMe)I-NH2, Figure 6) displayed a
more active than the parent peptide compstatin. It is likely
that the fused aromatic ring of the non-natural amino acid
at position 4 is involved in the hydrophobic interaction
with the binding site of C3, and also contributes to the
formation of the hydrophobic cluster of compstatin.
Furthermore, the incorporation of 1-methyltryptophan
(1MeW) at position 4 yields a compstatin variant (Ac-I[CV
(1MeW)QDWGAHRC]T-NH2, IC50 = 205 nM; Figure 5) with a
264-fold increase in potency over the original compstatin in
inhibiting complement activation [34]. A detailed analysis of
structure-kinetic relationship study has shown that increas-
ing the hydrophobicity at position 4 can improve the sta-
bility of the C3b–compstatin complex [38]. It is suggested
that the introduction of a methyl group to the indole
nitrogen of Trp-4 contributes to a favorable value of the Figure 6. The N-methylation scan yielded a potent compstatin analog, termed
free energy due to the formation of additional hydrophobic as CP20.
 EXPERT OPINION ON DRUG DISCOVERY 5

1000-fold increase in both potency (IC50 = 62 nM) and binding Table 1. The six pharmacophore features of compstatin [41].
affinity for C3b (KD = 2.3 nM) over that of the original comp- Radius
statin. Biophysical analysis using surface plasmon resonance ID Feature Center (Å)
and isothermal titration calorimetry suggests that the F1 Aromatic ring Center of mass of W4 indole ring 1.2
F2 Hydrogen-bond Carbonyl oxygen on the Q5 side 0.8
improved binding affinity originates from more favorable acceptor chain
free conformation and stronger hydrophobic interactions. F3 Hydrogen-bond donor Amide nitrogen on the Q5 side chain 0.8
The considerable efforts on the generation of complement F4 Hydrogen-bond Carbonyl oxygen on the D6 side 2.2
acceptor chain
inhibitors led to the discovery of a great number of compsta- F5 Hydrogen-bond donor Indole nitrogen of W7 0.8
tin analogs. A quantitative structure–activity relationship F6 Hydrophobe Centroid of two Sγ atoms of C2 and 0.7
(QSAR) model was generated to correlate key physicochemical C12
and geometrical properties of compstatin analogs with their
inhibitory activities [40]. The number of aromatic bonds in the
non-human primates showed that these analogs have highly
side chain of residue 4 (b_ar_4), the hydrophobic patch size
beneficial plasma half-life values (CP20, half life = 9.3 h; CP30,
near the disulfide bond (hyd_patch_surf), the solvent-accessi-
half life = 10.1 h; CP40, half life = 11.8 h). In addition, there
ble surface area occupied by nitrogen atoms of basic amino
are strong indications that these compstatin analogs actually
acid residues (base_N_surf), and the hydrophobicity of residue
follow a target-driven model since C3 is a highly abundant
4 (polar_4) correlate strongly with the inhibitory activity of
plasma protein.
compstatin analogs (Figure 7). This simple QSAR model is
In 2014, conjugates of complement inhibitor compstatin
highly accurate and statistically significant, thus provides the
and albumin binding molecules were reported [46]. This
basis for the rational design of active compstatin analogs even
study resulted in the most potent C3b ligand with subnano-
in the absence of a ligand-receptor complex. Later, a 3D
molar binding affinity (KD = 150 pM) in Figure 8. The interac-
pharmacophore model was identified as a filter with great
tions of ABM2-CP20 with albumins from different species
sensitivity and specificity to discriminate 82 active compstatin
(human, baboon, bovine, rabbit and mouse) were character-
analogs [41]. Taking advantage of the co-crystal structure of
ized. The competition experiment showed that ABM2-CP20
C3c-compstatin complex, six structural features were built into
binds primarily to site II on HSA. Albumin binding molecule
individual pharmacophore points based on the two most
is able to improve the plasma protein binding of ABM2-CP20,
active compstatin analogs (Table 1). Consistent with the
which suggests its favorable pharmacokinetic property.
QSAR study, the aromatic ring of residue 4 (F1) and the
The site specific PEGylation of compstatins was reported in
hydrophobe on the disulfide bond (F6) were identified as the
an effort to increase the half life in vivo [47]. A two-arm
most critical pharmacophore features in determining the inhi-
branched PEG chain (40 kDa) was conjugated to the lysine ε-
bitory activity. Owing to the enriched knowledge in the struc-
amino group of Ac-CP40-K, and the N-terminal α-amino group
tural features, tremendous efforts have been devoted to the
of CP40, respectively (Figure 9). In a preliminary in vivo study,
computational and rational design of new compstatin variants
the pharmacokinetic profile of pegylated compstatin has
over the years [42–44].
shown a significant feature for the treatment of chronic dis-
 
log10 IC50;Rel ¼ 0:1573b ar 4 þ 0:0034hyd patch surf eases. The half life is around 5.5 days (increased by over 11
þ0:0058base N surf  0:1266polar 4 folder compared with the non-pegylated peptide CP40) in


1:8572 n¼50; R2 adj ¼ 0:89; Q2 ¼ 0:88; s¼ 0:3023; sCV ¼ 0:3167: baboons indicating a feasible option for clinical

New generations of the compstatin family featured with sub-

nanomolar affinity and enhanced pharmacokinetic properties
were reported [45]. The N-terminal modifications of comp-
statin CP20 with non-proteinogenic amino acids resulted in
two potent analogs Sar-I[CV(1MeW)QDW-Sar-AHRC](NMe)I-
NH2, termed as CP30; (D-Tyr)-I[CV(1MeW)QDW-Sar-AHRC]
(NMe)I-NH2, termed as CP40). CP40 is so far the strongest
C3 ligand with subnanomolar binding affinity (KD = 0.5 nM).
The computational modeling analysis indicated that the
N-terminally modified compstatin analogs formed additional
contacts with a shallow pocket in the binding site of C3c. The
substitution of non-proteinogenic amino acids is expected to
afford an additional benefit of maintaining protection against Figure 8. The conjugation to albumin-binding molecule yielded a more potent
exopeptidases. Significantly, pharmacokinetic evaluation in compstatin analog, termed as ABM2-CP20.

log10[IC50,Rel] = 0.1573b_ar_4 + 0.0034hyd_patch_surf + 0.0058base_N_surf – 0.1266polar_4 –

1.8572 (n = 50, R2adj = 0.89, Q2 = 0.88, s = 0.3023, sCV = 0.3167.)

Figure 7. QSAR model of compstatin ([IC50,Rel]: IC50 relative to that of the parent compstatin).
6 Y. HUANG

Figure 9. The site specific PEGylation of compstatins.

administration; the flat concentration curve shows its potential step in the activation of the human complement system
for the systematic inhibition of complement activation. makes compstatin an attractive therapeutic candidate for the
treatment of inflammatory diseases. In 2000, compstatin was
evaluated to treat protamine/heparin-induced complement
4. Therapeutic development of compstatins activation, the inflammatory response commonly induced by
cardiac surgery and cardiopulmonary bypass [53]. A combina-
Compstatin has shown high species selectivity to human and
tion of bolus injection and infusion of compstatin at a total
primate complement systems, which limits the preclinical
dose of 21 mg/kg in baboons can completely inhibit the
development in animal models using lower mammalian spe-
generation of C3 activation products without adverse effects
cies [48]. The SPR analysis showed that compstatin binds to C3
on heart rate, blood pressure or hematological parameters. In
proteins from human and baboon, however, it does not bind
2002, compstatin (Ac-I[CVVQDWGHHRC]T-NH2) was used to
to C3 proteins form mouse or rat. In addition, compstatin does
study the role of complement in Escherichia coli induced
not bind to two structural homologs of C3, human C4 and C5.
inflammatory responses [54]. It was found that compstatin
Therefore, the inhibitory action of compstatin on complement
can efficiently reduce Escherichia coli induced oxidative burst
activation is solely due to its activity against C3. Recently, the
and MPO release, as well as the complement activation in
molecular dynamics simulations suggested that the rat C3
whole blood. In addition, IL-8 secretion was abolished by the
protein undergoes local conformational changes, which dis-
combination of compstatin and anti-CD14.
rupt polar and nonpolar interactions with compstatin and
Compstatin has shown great therapeutic potential for the
reduce the stability of the complex [49]. So far, compstatin
treatment of transplantations to reduce complement-
analogs have been shown to be safe and effective in a series
mediated organ injury and xenograft rejection. In 1999, pig
of ex vivo and in vivo experiments, and hold great promise for
kidneys, which were perfused with fresh human blood con-
further clinical investigations [15,50]. As the first-in-class com-
taining compstatin, had significantly longer graft survival [55].
plement inhibitor, compstatin can offer great therapeutic
C3 activation products and terminal complement complex
opportunities with regard to many diseases, in which inap-
were effectively controlled by the administration of compsta-
propriate or uncontrolled activation of complement is
tin. This study suggests that compstatin may be a useful
involved in the disease pathogenesis (Table 2).
clinical candidate to delay or prevent hyperacute rejection. In
Studies using animal models have shown that compstatin
2008, compstatin (Ac-I[CV(1MeW)QDWGAHRC]T-NH2) was
has excellent safety and efficacy profiles as a complement
used to treat xenogeneic instant blood-mediated inflamma-
inhibitor, due to its ability to specifically block the comple-
tory reaction (IBMIR) in a non-human primate model of pan-
ment activation at the C3 level [4,5]. The ability to inhibit a key
creatic islet transplantation [56]. The in vitro study showed
that compstatin significantly reduced the binding of C3b/
Table 2. Studies of compstatin used in disease models. iC3b to the islets, and completely inhibited the immediate
Timeline Disease models Subjects Reference destructive immunoglobulin-triggered complement activation.
1998 Extracorporeal Human blood (in vitro) [59] In a human model of clinical islet transplantation, it has been
circulation shown that compstatin (Ac-I[CV(1MeW)QDWGAHRC]T-NH2)
1999 Transplantation Pig kidney (ex vivo) [55]
2000 Inflammation Baboon (in vivo) [53] can block the antibody-mediated complement attack on the
2002 Inflammation Human blood (in vitro) [54] islets, indicating compstatin as a prime candidate for eliminat-
2007 Age-related macular Human patients (phase 1) [51,66] ing complement damage to the islet graft [57].
degeneration
2008 Transplantation Pig/human islet (in vitro) [56,57] It has been known that the artificial surface and biomater-
2008 Age-related macular Rabbit, monkey (in vivo) [52,67] ials used in many clinical settings can cause whole blood
degeneration inflammatory reaction due to complement and cellular activa-
2010 Sepsis Baboon (in vivo) [69]
2010 Hemodialysis Human blood (ex vivo) [63] tion [58]. Compstatin is a promising therapeutic agent to
2013 Paroxysmal nocturnal Patient-derived erythrocytes (in [47] inhibit complement-associated bioincompatibility reactions in
hemoglobinuria vitro), monkey (in vivo) clinical applications. In 1998, compstatin was evaluated in two
2015 C3 glomerulopathy Human blood (in vitro) [71]
2016 Paroxysmal nocturnal Human patients (phase 1) [74] in vitro models of extracorporeal circulation using whole
hemoglobinuria human blood [59]. Compstatin (I[CWQDWGAHRC]T) effectively
2016 Periodontitis Monkey (in vivo) [72] inhibited the complement activation, preventing the
 EXPERT OPINION ON DRUG DISCOVERY 7

activation and binding of polymorphonuclear leukocytes to study showed that complement inhibition with compstatin
the biomaterial surface. It has been shown that complement (Ac-I[CV(1MeW)QDWGAHRCT]I-NH2) reduced erythrocyte bind-
activation on a model biomaterial surface is mainly mediated ing and bacterial C3 opsonization [70]. Therefore, compstatin
by the alternative pathway [60]. Independent of the types of is a potentially important therapeutic agent for blocking the
biomaterial surface, compstatin was found to reduce the acti- harmful effects of complement activation products during the
vation of neutrophils in polymer-exposed blood, thus reduce organ failure stage of severe sepsis.
the risk of biomaterial-mediated inflammatory reactions [61]. Amyndas Pharmaceuticals founded by Professor John
The further study showed that the artificial surface markedly Lambris has devoted to the development of next-generation
induced a broad spectrum of proinflammatory chemokines Compstatins for clinical applications. PNH is chronic, comple-
and growth-factors, which was largely reduced by the treat- ment-mediated, intravascular hemolysis which affects 8,000–
ment of compstatin (Ac-I[CV(1MeW)QDWGAHRC]T-NH2) [62]. 10,000 people in North America and Europe. CP40 demon-
Therefore, it is a promising therapeutic strategy for compsta- strated its ability to efficiently prevent C3 activation and opso-
tins to prevent biomaterials trigged complement activation in nization on PNH erythrocytes in vitro (IC50 ~ 4 µM), while
patients on hemodialysis. In 2010, an ex vivo hemodialysis saturating inhibitor concentration could be reached with
model was used to evaluate compstatins (Ac-I[CV(1MeW) CP40 through repetitive subcutaneous administration in cyno-
QDWGAHRC]T-NH2 and Ac-I[CV(1MeW)QDWSarAHRC]I-NH2, molgus monkeys [47]. In 2014, both the European Medicines
termed as CP10) for the treatment of complement-related Agency (EMA) and the U.S. Food and Drug Administration
adverse effects [63]. It has been shown that compstatins are (FDA) granted AMY-101 (based on CP40) as an orphan drug
able to attenuate the hemodialysis filter fibers induced com- designation for the treatment of PNH. The first-in-human clin-
plement activation, and reduce the tissue factor dependent ical study of AMY-101 has been initiated in 2017
procoagulant activity of polymorphonuclear leukocytes during (NCT03316521). Dense deposit disease (DDD) and C3 glomer-
hemodialysis. ulonephritis (C3GN) are rare forms of glomerulonephritis
Compstatin has been investigating for the treatment of which result from abnormal regulation of the alternative com-
local and systemic inflammation in age-related macular plement pathway. CP40 is able to prevent complement-
degeneration (AMD), which is mediated by the deregulated mediated lysis of sheep erythrocytes in sera from C3 glomer-
action of the alternative pathway of the complement system ulopathy (C3G) patients, which holds the promise to C3G
[64,65]. The complement inhibitors may offer a new paradigm patients as a disease-specific, targeted therapy [71]. In 2016,
to prevent, retard, or even reverse AMD, a leading cause of Amyndas Pharmaceuticals announced that AMY-101 was
global blindness [66]. The treatment of compstatin (Ac-I[CV granted an orphan drug designation by EMA and FDA for
(1MeW)QDWGAHRC]T-NH2) on cynomolgus monkeys with the treatment of C3G. Human periodontitis is a prevalent
early-onset macular degeneration can suppress the formation chronic oral disease for nearly half of adults, which is asso-
of drusen, which contains active complement molecules and ciated with over-activation of complement. CP40 has been
represents a risk factor for dry-type AMD [67]. As one of a few shown to inhibit pre-existing chronic periodontal inflamma-
drugs discovered in academia, compstatin was licensed from tion and osteoclastogenesis in non-human primates, suggest-
the University of Pennsylvania to Potentia Pharmaceuticals in ing its potential as a novel adjunctive anti-inflammatory
2006 in the attempt to enter clinical trials. In 2007, Potentia therapy for treating human periodontitis [72]. In addition,
Pharmaceuticals started a Phase I clinical trial (NCT00473928) CP40 has been under evaluation as a potential treatment of
using a compstatin analog POT-4 for the treatment of neovas- complications of hemodialysis and ABO incompatible kidney
cular AMD [68]. Later Potentia signed a licensing and purchase transplantation [73].
agreement with Alcon to develop its leading drug candidate, Apellis Pharmaceuticals acquired Potenita in 2014 and is
POT-4. In 2012, Alcon completed a Phase II clinical trial devoted to the clinical development of APL-1 (POT-4 formu-
(NCT01157065) using a compstatin analog AL-78898A for the lated for inhaled administration) and APL-2 (PEGylated APL-1,
treatment of exudative AMD. In 2013, Alcon terminated a formulated for subcutaneous and intravitreal administration)
multicenter Phase II clinical trial (NCT01603043) using AL- in several diseases and conditions including COPD and AMD.
78898A for the treatment of geographic atrophy associated Apellis completed phase 1b study of APL-2 for PNH patients
with AMD. Compstatin was administrated via single intravi- with daily subcutaneous administration [74]. On 20 December
treal injection, and the gel deposits were formed to slowly 2016, FDA granted Fast Track designation to the development
release active drug into the vitreous cavity over several program for APL-2 in the treatment of patients with PNH, who
months. continue to experience hemolysis and require RBC transfu-
Compstatin induced complement inhibition was investi- sions despite receiving therapy with eculizumab. On 10
gated as a promising approach for treating sepsis and multiple August 2017, Apellis announced the closing of $60 million
organ failure, which involve massive activation of coagulation series E finacing that would be used to advance trials of
and complement cascades [69]. Compstatins (Ac-I[CV(1MeW) APL-2 in PNH. Based on these encoraging efforts, compstatin
QDWGAHRCT]I-NH2) was administered after Escherichia coli is likely to be further developed for the treatment of PNH.
challenge in a baboon model of sepsis-induced multiple
organ failure. Compstatin infusion rapidly inhibited C3a and
5. Conclusion
C3b generation in septic baboons, reduced sepsis-induced
leucopenia and thrombocytopenia, and lowered the accumu- All in all, compstatin family has shown beneficial effects in a
lation of macrophages and platelets in organs. The further number of disease models, and it holds the promise as a
8 Y. HUANG

versatile therapeutic drug for implications against unregulated great potential for next generation complement therapeutics
complement activation in human and primates. We can fore- to benefit patients in the coming years.
see that more and more studies using compstatin as a valu-
able tool in immunological and translational research for
blocking the effect of the complement cascade. It is exciting Acknowledgments
to see clinical advances of next-generation compstatins in new This manuscript is dedicated to Professor John D Lambris for his contribution
therapeutic implications for a variety of disease conditions. in the discovery and development of compstatin. The author offers his
thanks to Professor Lambris (Department of Pathology & Laboratory
Medicine at University of Pennsylvania, USA) and Professor Daniel Ricklin
(Department of Pharmaceutical Sciences at University of Basel, Switzerland).
6. Expert opinion
Considering long-term treatment in chronic diseases (such as
Funding
PNH, aHUS), there is a critical need to develop therapies with
simple administration and reduced dose schedules. Substantial This manuscript has not been funded.
challenges still remain to develop effective therapeutics which
can maintain systemic complement inhibition, since the circulat-
ing levels of complement proteins are usually high and turnover Declaration of interest
rates are relatively rapid, which require the frequent dosing of The author of this manuscript is an employee of WuXi AppTec Inc. They
complement inhibitors. Therefore, it is very essential for new have no other relevant affiliations or financial involvement with any
generations of compstatin derivatives with favarable features organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript apart
and feasibility as chronic complement therapeutics such as from those disclosed. Peer reviewers on this manuscript have no relevant
improved pharmacokinetics and suitable dosing routes. Further financial or other relationships to disclose.
study is needed to optimize in vivo performance of compstatins
as complement inhibitors, which will greatly facilitate the devel-
opment of chronic complement therapeutics to modulate the References
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