Infectious Diseases

Sepis, SIRS

I/R Injury

Psoriasis

Myasthenia Gravis

SLE

PNH

Hereditary Angioedema

Multiple Sclerosis

Trauma, Burn Injury

Capillary Leak Syndrome

Obesity, Diabetes

Cancer

Alzheimer’s Disease, Stroke, Schizophrenia,

Epilepsy

AMD,Glaucoma,

Diabetic Retinopathy

Asthma, Allergy, ARDS, Cystic Fibrosis

Myocardial Infraction

aHUS (and HUS), MPGN-II Lupus Nephritis

Crohn’s Disease

Rheumatoid Arthritis

Atherosclerosis Vasculitis

Transplant Rejection Fetal Loss Biomaterial Reactions (Hemodialysis, Implants...)

INTELLIGENT INSIGHTS. SMART RESULTS.

Complement Disorders and Potential Therapiesfor Complement Mediated Diseases: A Spotlight

There is a renewed interest in pursuing the complement

pathway as drug targets based on the success of

eculizumab (Soliris; Alexion Pharmaceuticals) in the

treatment of an orphan disease, paroxysmal nocturnal

haemoglobinuria. There are now multiple anti-

complement drugs in the market, including Soliris/Alexion

(PNH and aHUS), Cinryze (HAE), Berinert and

Haegarda/CSL Behring (HAE), Ruconest/Pharming (HAE),

and many more are being developed across a broad

spectrum of diseases.

Figure 1. Complement system mediated diseases

The complement system is considered to be an immune mediated defense against infection and is an important driver

of inflammation. However, uncontrolled activation of complement can lead to local and/or systemic inflammation

and tissue damage causing inflammatory, autoimmune and degenerative diseases. More than 50 conditions are now

widely recognized as diseases with demonstrated or suspected involvement of the complement system.

Complement pathway and its regulation

The complement system is a tightly regulated network of

more than 30 proteins, largely designated by the letter C

and number in the order of discovery (e.g., C1, C2, C3,

etc.). These proteins are present as an inactive form or

zymogens in blood or as bound to membranes. Sequential

cascade of enzymatic reactions cleaves and activates

these proteins to form potent anaphylatoxins that elicit

physiological responses ranging from chemo attraction

to apoptosis.

Figure 2. Complement system

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The SMARTImmunology Newsletter Team: Anupam Goyal, PhD, Anil Lele, Rohit Katoch

Copyright © 2017 SMARTANALYST

Volume 1, Issue 2 Immunology Newsletter | August 2017

C3

C3bBb3b

FB and FD FB and FDMASPsC1r and C1s

FB and FD

Lectin pathway Alternative pathway initiation

Alternative pathway amplification

Terminal pathway

C3bBb

C3(H2O)BbC3BbP

C4b2b

C4b2b3b

Classical pathway

C3(H2O)

C3b

C2C4

C3

C5

C3b

iC3b

C3a

C3bg

C5a

C5b MAC

Extrinsic proteases

MBL Fcn CL-11

FP

C6, C7, C8, C9n

Extrinsic proteases

CD35 and FI

FPC1q

AssociationCleavageTransformation

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Volume 1, Issue 2 Immunology Newsletter | August 2017

Complement activation is usually initiated by the

interaction of several pattern-recognition receptors with

foreign surface structures. Depending on the activation

trigger, the complement cascade follows one of three

pathways: the classical, lectin or alternative pathway.

All three pathways converge at the cleavage of

complement C3.

• The Classical Pathway (CP) is initiated by antibody

complexes. These complexes are formed by binding

of pathogens to IgG or IgM. Antibody complex binds

to the C1 complex and activate C1s and C1r. C1s then

cleaves C4 and C2 to form the C3 convertase.

• The Lectin Pathway (LP) is activated by binding of

mannose binding lectin (MBL) or Ficolin to

carbohydrates on surfaces of pathogens including

yeast, bacteria, parasites and viruses. This pathway is

activated similar to the classic pathway except that

lectin replaces the immune complex and mannan-

binding lectin–associated proteases (MAPS) replace

C1 enzymatic activity which activate C4 and C2 and

form the C3 convertase.

• The Alternative Pathway is considered to be the

dominant contributor to the overall complement

response and is triggered by carbohydrates, lipids

and proteins found on the foreign surfaces such as on

viruses, fungi, bacteria, and parasites. The alternative

pathway is divided into two arms, one that initiates

complement activation and invokes pattern

recognition (that is, by properdin) or hydrolysis of C3

to form C3 convertase and the other that mediates

amplification independent of the initiating

mechanism.

The common pathway starts with the cleavage of C3 into

its active fragments by C3 convertases, C3a and C3b. C3b

complexes with the C3 convertases to form the C5

convertases. The C5 convertases cleave C5 to form C5a

and C5b. The anaphylatoxins C3a, C3b and C5a, are potent

inflammatory mediators that initiate various processes

including formation of membrane attack complex (MAC),

which culminate in the stimulation of immune cells and

the elimination of the pathogen.

Impact of complement dysregulation

• Complement dysregulation may include both an

inappropriate initiation of the cascade or deficiencies

in specific components or regulators.

Table 1. Impact of complement dysregulation

Complement Dysregulation Diseases Caused

Deficiency in Complement Proteins

Excessive Complement Activation (Dysregulated Modulation)

• aHUS, PNH, Age-related Macular Degeneration (AMD)

• Other diseases include Alzheimer’s syndrome, Asthma and the Acute Response Distress Syndrome (ARDS).

Complement pathway as drug targets and drugs in development

The role of complement in the pathophysiology of major diseases makes it an interesting target for the pharmaceutical industry. The complement cascade offers various points of intervention at almost any level starting from initiation and primary activation to amplification, effector signalling, and lysis.

• Upstream intervention at the level of specific initiation steps of complement pathway may help in regulating uncontrolled activation of classical, lectin pathways and alternative pathways. The inhibition of C1r/s by C1 esterase inhibitor (C1-INH) may effectively shut down complement activation and subsequent generation of effector molecules caused by the classical pathway without affecting the protective functions of the other pathways.

• Blocking the common pathway at the level of C3 activation, either by blocking C3 directly (e.g., using compstatin) or by acting on the convertase, will efficiently block all activation, amplification, and effector routes independent of the disease mechanism. This may pose a higher risk of blocking beneficial complement functions.

• Blockage at the terminal end can be very effective in eliminating specific function (depending on the target) without blocking other complement activity. For example, blocking C5 (Eculizumab) impairs the formation of the MAC and inflammatory signalling by C5a, whereas only the signalling function is blocked by targeting the C5a receptor (C5aR) with antagonists such as PMX53.

A number of promising candidates for the clinical substitution, inhibition or modulation of complement are in development.

• Lupus• Hemolytic Uremic Syndrome

(HUS), etc.

Volume 1, Issue 2 Immunology Newsletter | August 2017

Table 2. List of complement therapeutics that are marketed or are in clinical development (> Phase II)

Diseases Asset Phase Company

C3 & sCR1

Age-related Macular Degeneration APL-2 Phase II Apellis Pharma Common Pathway Target – C5aR

ANCA Associated Vasculitis CCX-168 Phase III (Orphan Drug Status) ChemoCentryx Atypical Hemolytic Uremic Syndrome CCX-168 Phase II (Orphan Drug Status) ChemoCentryx

C3 Glomerulopathy CCX-168 Phase II (Orphan Drug Status) ChemoCentryx Sepsis IFX-1 Phase II InflaRx

Hidradenitis Suppurativa IFX-1 Phase II InflaRx Common Pathway -

Target –

C5

Atypical Hemolytic Uremic Syndrome

Eculizumab

Marketed (Orphan Drug Status)

Alexion

ALXN-1210

Phase III

Alexion

Coversin

Phase II

Akari Therapeutics

Paroxysmal Nocturnal Haemoglobinuria

Eculizumab

Marketed (Orphan Drug Status)

Alexion

ALN-CC5

Phase II

Alnylam Pharma

ALXN-1210

Phase III (Orphan Drug Status)

Alexion LFG 316

Phase II

Morphosys/Novartis

Coversin

Phase II (Fast-track and Orphan

Drug Status)

Akari Therapeutics

RA101348

Phase II (Orphan Drug Status )

Ra Pharmaceuticals

RO-7112689

Phase II

Roche

Myasthenia Gravis

Eculizumab

Pre-registration (Orphan Drug Status)

Alexion

Neuromyelitis Optica

Eculizumab

Phase III (Orphan Drug Status)

Alexion

Stec HUS

Eculizumab

Phase II/III (Orphan Drug Status)

Alexion

Acute Antibody Mediated Rejection

Eculizumab

Phase II

Alexion

Age-related Macular Degeneration

LFG 316

Phase II

Morphosys/Novartis

Zimura

Phase III

Ophthotech

Polypoidal Choroidal Vasculopathy

Zimura

Phase II

Ophthotech

Panuveitis

LFG 316

Phase II

Morphosys/Novartis

Transplant Associated Microangiopathy

LFG 316

Phase II

Morphosys/Novartis

C1 Esterase Inhibitor (C1-INH)

Hereditary Angioedema

C1 INH (Human)

Marketed

CSL Behring

C1 INH (Human)

Marketed (Orphan Drug Status)

Shire Viropharma

Conestat alfa

Marketed (Orphan Drug Status)

Pharming

Acute Antibody Mediated Rejection

C1 INH (Human)

Phase III (Orphan Drug Status)

Shire Viropharma

Target –

MASP-2

Atypical Hemolytic Uremic Syndrome

OMS 721

Phase III (Fast Track Status and Orphan Drug Status)

Omeros

Membranoproliferative Glomerulonephritis

Phase II

IgA Nephropathy

Phase II (Fast Track Status and

Orphan Drug Status)

Transplant Associated Microangiopathy

Phase II (Orphan Drug Status)

Thrombotic Thrombocytopenic Purpura

Phase II

Lupus Nephritis

Phase II

C3 Glomerulopathy Phase II

C3- Conv

Age-related Macular Degeneration Lampalizumab Phase III Roche

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Volume 1, Issue 2 Immunology Newsletter | August 2017

Risks associated with complement therapies:

The biggest risk associated with complement therapies is

that a drug blocking a complement pathway can

significantly increase the risk of infections and other

immune mediated diseases.

• Drugs that inhibit the classical pathway may affect

the clearance of immune complexes and apoptotic

cells

• Inhibition of the activation pathways may disrupt an

adaptive immune response and recurrent infections

may become life-threatening

• Anti-complement drugs may also disrupt normal lipid

metabolism or interfere with the healing and

resolution of injuries

These potential consequences need to be considered

while deciding whether and when to use an anti-

complement drug and which part of the system to target.

With appropriate prophylactic measures such as

immunization and antibiotic therapy, and with careful

consideration of the target, these consequences can be

managed. Research is ongoing to devise strategies to

inhibit complement without risking significant infections

and immune mediated diseases. Some strategies being

considered are:

• Delivering therapies directly to disease sites so that

systemic inhibition is avoided. One such example is

C3 blocker compstatin and an antibody antigen-

binding fragment (Fab) directed against Factor D

(FD), administered intravitreally for the treatment of

AMD (currently in Phase III clinical trials)

• Treating acute conditions by inhibiting complement

transiently

Conclusion

While the role of complement system has been

demonstrated in a number of diseases, the extent of the

role played by the complement system in the

pathophysiology of certain diseases, such as Myocardial

infarction, Myasthenia gravis, and Asthma remains

unclear. Therefore, further studies are needed to

understand the extent of role of complement system in

these diseases and benefits that can be derived by

modulating the pathway. As the role of complement

system becomes clearer, newer treatment options will be

developed.

References:

1. B. Paul Morgan and Claire L. Harris. Complement, a target for

therapy in inflammatory and degenerative diseases. Nature

Reviews Drug Discovery. Volume 14 , December 2015: 857

2. Horiuchi and Tsukamoto. Complement-targeted therapy:

development of C5- and C5a-targeted inhibition. Inflammation

and Regeneration 2016, 36:11

3. Holers et al. Complement Therapeutics, Advances in Experimental

Medicine and Biology 735

4. Daniel Ricklin and John D Lambris. Complement-targeted

therapeutics. Nat Biotechnol. 2007 November; 25(11):

1265–1275

5. Jason R Dunkelberger, Wen-Chao Song. Complement and its role in

innate and adaptive immune responses. Cell Research (2010)

20:34-50

6. J. Vidya Sarma and Peter A. Ward. The Complement System. Cell

Tissue Res. 2011 January; 343(1): 227–235

7. Daniel Ricklin, Edimara S. Reis and John D. Lambris. Complement

in disease: a defence system turning offensive. Nature Reviews

Nephrology. Volume 12, July 2016: 383

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The SMARTImmunology Newsletter Team: Anupam Goyal, PhD, Anil Lele, Rohit Katoch

Copyright © 2017 SMARTANALYST