Table Of ContentAdvances in Experimental Medicine and Biology
Volume 735
Editorial Board:
NATHAN BACK, State University of New York at Buffalo, NY, USA
IRUN R. COHEN, The Weizmann Institute of Science, Rehovat, Israel
ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA
JOHN D. LAMBRIS, University of Pennsylvania, Philadelphia, PA, USA
RODOLFO PAOLETTI, University of Milan, Milan, Italy
For further volumes:
http://www.springer.com/series/5584
John D. Lambris • V. Michael Holers • Daniel Ricklin
Editors
Complement Therapeutics
Editors
John D. Lambris V. Michael Holers
Department of Pathology Departments of Medicine
and Laboratory of Medicine and Immunology
University of Pennsylvania University of Colorado
Philadelphia, PA, USA School of Medicine
Aurora, CO, USA
Daniel Ricklin
Department of Pathology
and Laboratory of Medicine
University of Pennsylvania
Philadelphia, PA, USA
ISSN 0065-2598
ISBN 978-1-4614-4117-5 ISBN 978-1-4614-4118-2 (eBook)
DOI 10.1007/978-1-4614-4118-2
Springer New York Heidelberg Dordrecht London
Library of Congress Control Number: 2012945942
© Springer Science+Business Media New York 2013
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Preface
The past decade has witnessed a new surge in the development of complement-targeted therapeutics,
fueled by the successful launch of the fi rst complement pathway-speci fi c inhibitors and the discovery
of both orphan and highly prevalent diseases with contributions from complement. Apart from offer-
ing new hope for patients suffering from such diseases, the study of complement pathways, mutations,
and de fi ciencies also teaches us important lessons about the role of complement in health and disease
as well as allows us to re fi ne our models and tools for applied and basic research. These exciting
developments were at the center of the Fifth International Complement Therapeutics Conference
(June 22–27, 2011) in Rhodes, Greece, where expert scientists from academia, clinical institutions,
and the pharmaceutical industry convened to discuss current progress, challenges, trends, and emerg-
ing applications in complement therapeutics. This volume represents a collection of highlights from
this conference covering topics from functional and molecular descriptions of complement targets to
development of complement-directed inhibitors, drug targeting to cells, tissues, and biomaterials,
emerging clinical applications (e.g., in ocular, dental, and transplantation medicine), as well as novel
diagnostic approaches.
We would like to express our sincere thanks to all the contributing authors for the time and effort
they have devoted to writing exceptionally informative chapters in a book that will have a signi fi cant
impact on the fi eld of complement-related drug discovery and development. We would also like to
thank Rodanthi Lambris for collating the chapters and Dimitrios Lambris of Conferex LLC for man-
aging the organization of this exceptional meeting. Finally, we also thank Samantha Lewis of Springer
Publishers for her supervision in this book’s production.
Philadelphia, PA, USA John D. Lambris
Aurora, CO, USA V. Michael Holers
Philadelphia, PA, USA Daniel Ricklin
v
Contents
1 Progress and Trends in Complement Therapeutics ...................................................... 1
Daniel Ricklin and John D. Lambris
2 Inhibition of the Serine Proteases of the Complement System .................................... 23
Péter Gál, József Dobó, László Beinrohr, Gábor Pál, and Péter Závodszky
3 The Role of MASP-1/3 in Complement Activation ....................................................... 41
Hideharu Sekine, Minoru Takahashi, Daisuke Iwaki, and Teizo Fujita
4 Membrane-Bound Complement Regulatory Proteins as Biomarkers
and Potential Therapeutic Targets for SLE ................................................................... 55
Nibhriti Das, Bintili Biswas, and Rohan Khera
5 DAF as a Therapeutic Target for Steroid Hormones:
Implications for Host–Pathogen Interactions................................................................ 83
Bogdan Nowicki and Stella Nowicki
6 Targeting gC1qR Domains for Therapy Against
Infection and Inflammation ............................................................................................ 97
Berhane Ghebrehiwet, Jolyon Jesty, Rama Vinayagasundaram,
Uma Vinayagasundaram, Yan Ji, Alisa Valentino, Nithin Tumma,
Kinga H. Hosszu, and Ellinor I.B. Peerschke
7 The Alternative C5a Receptor Function ........................................................................ 111
Hiroshi Nishiura
8 The Effects of Selective Complement and CD14 Inhibition
on the E. coli-Induced Tissue Factor mRNA Upregulation,
Monocyte Tissue Factor Expression, and Tissue Factor
Functional Activity in Human Whole Blood ................................................................. 123
O.-L. Brekke, C. Waage, D. Christiansen, H. Fure, H. Qu,
John D. Lambris, B. Østerud, E.W. Nielsen, and T.E. Mollnes
9 CR2-Mediated Targeting of Complement Inhibitors:
Bench-to-Bedside Using a Novel Strategy for Site-Specific
Complement Modulation ................................................................................................. 137
V. Michael Holers, Bärbel Rohrer, and Stephen Tomlinson
10 Paroxysmal Nocturnal Hemoglobinuria and the Complement System:
Recent Insights and Novel Anticomplement Strategies ................................................ 155
Antonio M. Risitano
vii
viii Contents
11 Defective Complement Action and Control Defines Disease
Pathology for Retinal and Renal Disorders and Provides
a Basis for New Therapeutic Approaches ...................................................................... 173
Peter F. Zipfel and Nadine Lauer
12 C3 Glomerulonephritis/CFHR5 Nephropathy Is an Endemic
Disease in Cyprus: Clinical and Molecular Findings in 21 Families ........................... 189
Constantinos Deltas, Daniel Gale, Terence Cook,
Konstantinos Voskarides, Yiannis Athanasiou, and Alkis Pierides
13 Complement-Targeted Therapeutics in Periodontitis ................................................... 197
George Hajishengallis and John D. Lambris
14 Complement System Activation in Cardiac and Skeletal
Muscle Pathology: Friend or Foe? ................................................................................. 207
Maro Syriga and Manolis Mavroidis
15 Innate Immunity as Orchestrator of Bone Marrow Homing
for Hematopoietic Stem/Progenitor Cells ...................................................................... 219
Mariusz Z. Ratajczak, ChiHwa Kim, Janina Ratajczak,
and Anna Janowska-Wieczorek
16 Complement-Mediated Microvascular Injury Leads
to Chronic Rejection ........................................................................................................ 233
Mohammad A. Khan and Mark R. Nicolls
17 Targeting Complement at the Time of Transplantation ............................................... 247
Steven Sacks, Julia Karegli, Conrad A. Farrar, Elham Asgari,
Wilhelm Schwaeble, Wuding Zhou, and Richard A. Smith
18 Evaluation of the Blood Compatibility of Materials, Cells, and Tissues:
Basic Concepts, Test Models, and Practical Guidelines ............................................... 257
Kristina N. Ekdahl, Jaan Hong, Osama A. Hamad,
Rolf Larsson, and Bo Nilsson
19 Noninvasive Detection of Complement Activation
Through Radiologic Imaging .......................................................................................... 271
Joshua M. Thurman and Bärbel Rohrer
20 Highly Multiplexed Proteomic Platform for Biomarker Discovery,
Diagnostics, and Therapeutics ........................................................................................ 283
Michael R. Mehan, Rachel Ostroff, Sheri K. Wilcox,
Fintan Steele, Daniel Schneider, Thale C. Jarvis,
Geoffrey S. Baird, Larry Gold, and Nebojsa Janjic
21 Complement in Action: An Analysis of Patent Trends
from 1976 Through 2011 ................................................................................................. 301
Kun Yang, Robert A. DeAngelis, Janet E. Reed,
Daniel Ricklin, and John D. Lambris
Index .......................................................................................................................................... 315
Chapter 1
Progress and Trends in Complement Therapeutics
Daniel Ricklin and John D. Lambris
Abstract The past few years have proven to be a highly successful and exciting period for the fi eld
of complement-directed drug discovery and development. Driven by promising experiences with the
fi rst marketed complement drugs, increased knowledge about the involvement of complement in
health and disease, and improvements in structural and analytical techniques as well as animal models
of disease, the fi eld has seen a surge in creative approaches to therapeutically intervene at various
stages of the cascade. An impressive panel of compounds that show promise in clinical trials is mean-
while being lined up in the pipelines of both small biotechnology and big pharmaceutical companies.
Yet with this new focus on complement-targeted therapeutics, important questions concerning target
selection, point and length of intervention, safety, and drug delivery emerge. In view of the diversity
of the clinical disorders involving abnormal complement activity or regulation, which include both
acute and chronic diseases and affect a wide range of organs, diverse yet speci fi cally tailored thera-
peutic approaches may be needed to shift complement back into balance. This chapter highlights the
key changes in the fi eld that shape our current perception of complement-targeted drugs and provides
a brief overview of recent strategies and emerging trends. Selected examples of complement-related
diseases and inhibitor classes are highlighted to illustrate the diversity and creativity in fi eld.
1.1 Of Dogmas, Challenges, and Opportunities: The Changing
Field of Complement Research
It is very rare that complement research in general, and complement-directed drug discovery in par-
ticular, fi nds itself in the spotlight of media attention. Yet success stories about the off-label use of the
clinical anti-C5 antibody Eculizumab (Soliris, Alexion Pharmaceuticals) in the recent outbreak of
enterohemorrhagic E . coli in Europe (Laursen 2011 ; Lapeyraque et al. 2 011 ) or the promising results
with a soluble form of complement receptor 1 (sCR1, Mirococept) in transplantation medicine
(Sample 2010 ; Sacks and Zhou 2012 ) sparked a general interest in the fi eld. While this attention may
not persist at such a high level, it clearly underscores a new perception of the role of complement in
health and disease and highlights the promise of therapeutic intervention in the complement cascade.
Its upstream positioning in in fl ammatory processes and modulatory involvement in many (patho)
D. Ricklin (*) • J. D. Lambris
Department of Pathology and Laboratory Medicine , University of Pennsylvania , 401 Stellar Chance,
422 Curie Blvd , Philadelphia , PA 19104-6100 , USA
e-mail: [email protected]; [email protected]
J.D. Lambris et al. (eds.), Complement Therapeutics, Advances in Experimental Medicine and Biology 735, 1
DOI 10.1007/978-1-4614-4118-2_1, © Springer Science+Business Media New York 2013
2 D. Ricklin and J.D. Lambris
physiological processes indeed render complement an attractive target system. Research in recent
years has unraveled some of the mysteries about complement, shaken various dogmas, and revealed
fascinating new insights that are of importance for work related to complement-directed drug
discovery and beyond.
The most well-known function of complement is undoubtedly its role in microbial defense, where
it recognizes, tags, and helps to eliminate intruders such as bacteria, viruses, fungi, or parasites.
However, the surface recognition properties of complement are not restricted to pathogen-associated
molecular patterns (PAMPs) but also include danger-, damage-, or disease-related patterns of host
cells/tissues, immune complexes, or other foreign surfaces such as biomaterials. The severity and
outcome of complement response to these distinct triggers have to be tuned carefully and may include
opsonization, clearance, elimination, and/or danger signaling to in fl ammatory and adaptive systems.
This tuning is dependent on the context-speci fi c interplay of some 50 different proteins encompassing
pattern recognition proteins, proteases and their complement component substrates, soluble and
membrane-bound regulators, and various receptors (Ricklin and Lambris 2007a ; Ricklin et al. 2010 ) .
While often organized in three distinct initiation pathways, that is, the classical, lectin, and alternative
pathways (CP, LP, and AP, respectively; Fig. 1 .1 ), it becomes increasingly evident that there are
s everal interconnectivities and bypasses of the complement activation pathways; the involvement of
these pathways may therefore greatly vary depending on the trigger, as well as other factors.
Independent of the initiation route, ampli fi cation of the response by the AP, via formation of C3 con-
vertases that cleave the central component C3 into an anaphylatoxin (C3a) and an opsonin (C3b)
fragment, often causes the lion’s share of overall complement activation. Opsonization with C3b and
its degradation fragments iC3b and C3d facilitates both phagocytosis and adaptive immune signaling
via complement receptors CR1 to CR4. Deposited C3b not only fuels ampli fi cation by forming addi-
tional C3 convertases but also induces the generation of C5 convertases. Cleavage of C5 generates a
highly potent anaphylatoxin (C5a) with chemotactic and proin fl ammatory capacities as well as C5b,
which initiates the formation of the terminal complement complex (TCC) that may induce lysis of
susceptible cells or participate in signaling events. On host cells, a panel of “regulators of complement
activation” (RCA) and other inhibitors tame ampli fi cation and the accumulation of effector molecules
(Ricklin et al. 2 010 ; Carroll and Sim 2 011 ) . While the underlying processes within the cascade during
complement activation are highly complex and diverse, this level of complexity is not only essential
for an adequate response to distinct triggers but also offers a wide panel of potential targets for thera-
peutic intervention. Likewise, it becomes apparent that complement is by far not an isolated system
but heavily intertwined with other immune, defense, and in fl ammatory systems (e.g., toll-like
receptors, the cytokine network, adaptive immunity, and coagulation) and involved in homeostatic,
developmental, regenerative, or metabolic processes (Ricklin et al. 2010 ) . For example, some
proteases involved in coagulation (e.g., thrombin) or other networks (e.g., elastase) have been shown
to directly activate C3 and C5 (Fig. 1 .1 ) (Amara et al. 2 010 ; Oikonomopoulou et al. 2 012 ) .
At the same time, we are getting to know the key players, and thereby potential drug targets, in this
intricate complement network more closely than ever before. A wealth of high-resolution structural
models and sensitive functional assays have offered unprecedented insight into the shape, conver-
sions, and ligand interaction sites of complement components and revealed fascinating molecular
mechanisms that help explain the ability of complement to direct and tune its activities to the speci fi c
task and target surface. While crystallography is an essential driving force in this development,
orthogonal biophysical technologies like NMR, hydrogen/deuterium exchange mass spectrometry,
small-angle x-ray spectroscopy, electron microscopy, or interaction analysis by surface plasmon reso-
nance have fi lled many gaps and critically contributed to fully describe the structural and functional
complexity of complement proteins (Arlaud et al. 2 007 ; Ricklin and Lambris 2 007b ; Schuster et al.
2007 ; Perkins et al. 2 002 ) . Exemplary for this development is the structural characterization of C3,
which progressed from describing the C3d fragment (Nagar et al. 1998 ) to the publication of full
native C3 (Janssen et al. 2 005 ) and provided critical insight into the dynamic activation process and
