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Complement: driver of inflammation and therapeutic target in diverse diseases.

Event

Starts:

February
232015

09:00

Ends:

February
242015

17:00

Location

Kavli Royal Society Centre, Chicheley Hall, Newport Pagnell, Buckinghamshire, MK16 9JJ

Overview

Theo Murphy international scientific meeting organised by Professor Paul Morgan FMedSci and Professor Sir Peter Lachmann FMedSci FRS

Event details

This meeting will explore the remarkable recent advances in complement biology that have established its central role in pathogenesis, particularly for inflammatory diseases of later life. These findings have created novel diagnostic and therapeutic opportunities for targeting complement. We will bring together complement experts with leaders from cell biology, academic drug development and pharma to exploit these opportunities.

Download meeting programme

Recorded audio of the presentations will be available on this page after the event.

Attending this event

This is a residential conference, which allows for increased discussion and networking. It is free to attend, however participants need to cover their accommodation and catering costs if required.

Enquiries: Contact the events team

Schedule of talks

Session 1: Pathways to inflammation

4 talks Show detail Hide detail

Role of complement in autoimmunity - lessons from models and man

Professor Marina Botto FMedSci

Abstract

Complement has been shown to contribute to the immunopathology of several autoimmune diseases including systemic lupus erythematosus (SLE). Notwithstanding that, and somewhat paradoxically, complement also appears able to protect against autoimmunity since complement deficiencies, particularly of the early components of the classical pathway (C1q, C4, C1r and C1s) are associated with autoimmune disorders, particularly SLE. There are currently mainly two favoured mechanisms whereby deficiency or low levels of complement might lead to the autoimmune manifestations of SLE, and these are not mutually exclusive. One is the “waste-disposal” hypothesis whereby in the absence of complement apoptotic cells and immune complexes fail to be cleared effectively promoting further autoantibody production and inflammation. The second, “tolerance hypothesis”, relates to the role of complement in regulating both B and T cell immune responses. However, none of the current hypotheses can provide a unifying explanation of why C1q and not C3 deficiency predisposes to autoimmunity as both molecules play important roles in the clearance of apoptotic cells/immune complexes and exert analogous immunoregulatory roles. A possible explanation comes from our recent findings that C3 has an additional role: it can influence intracellular trafficking by inducing delayed lysosomal fusion of apoptotic cell cargo. C3 opsonisation can regulate the endocytic handling of apoptotic cells, a process that is essential for optimal T cell activation. In the absence of C3, the T cell proliferation in response to apoptotic cell-associated self-antigens is impaired and this may prevent the development of SLE. Hence C3 is uniquely required for both the generation of optimal T cell immune responses to self-antigens displayed on dying cells and their clearance. In the absence of C3, both arms of this process are impaired and autoimmunity is prevented.

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The membrane attack complex as an inflammatory trigger

Professor Paul Morgan FMedSci

Abstract

The final common pathway of all routes of complement activation involves the non-enzymatic assembly of a complex comprising newly formed C5b with the plasma proteins C6, C7, C8 and C9.  When assembly occurs on target cell membrane the forming complex inserts into and through the bilayer to create a pore, the membrane attack complex (MAC). On some targets, pore formation causes rapid lytic destruction; however, most nucleated cell targets resist lysis through a combination of ion pumps, membrane regulators and active recovery processes.  Cells survive but not without consequence. The MAC pore causes ion fluxes and directly or indirectly impacts several important signalling pathways that in turn activate a diverse series of events in the cell, many of which are highly pro-inflammatory.  Although this non-lytic, pro-inflammatory role of MAC has been recognised for thirty years, no consensus signalling pathway has emerged. Recent work has implicated specific signalling routes and, in some cells, inflammasome involvement opening the door to novel approaches to therapy in complement-driven pathologies.

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The amplification loop drives inflammation

Professor Sir Peter Lachmann FMedSci FRS

Abstract

The C3b feedback cycle, or C3 amplification loop, lies at the very heart of the complement system. It is the basis of the alternative complement pathway but also amplifies the classical and lectin pathways. It is a highly unusual triggered enzyme cascade where the concentrations of two enzymes that do not require to be activated (Factor I and Factor D) nevertheless influence greatly the extent of amplification. The C3 amplification loop also gives rise, as a side product, to the breakdown fragment, iC3b, whose reaction with CR 3 on neutrophils is required for all complement mediated inflammation and synergises with the action of C5a in recruiting and activating neutrophils the cells which are the principal mediators of complement mediated inflammation.

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The lectin activation pathway of complement in health and disease

Professor Hans-Wilhelm Schwaeble

Abstract

Of the three initiation routes of complement activation, the lectin pathway appears to be the most complex and least understood sensor and effector of the innate humoral immune response. The sensors of this pathway are pattern recognition molecules that direct activation of three different effector enzymes. They drive complement activation through two independently operating effector arms. While deficiencies of specific lectin pathway components were shown to lead to defects during embryonic development and predispositions to infectious disease, the specific pathophysiological contributions of each of the two lectin pathway effector arms to inflammatory pathologies is subject of current research. So far, it has been shown that one of the lectin pathway effector arms is exclusively involved in the pathophysiology of an inflammatory condition called ischaemia/reperfusion injury. The other lectin pathway effector arm was shown to critically contribute to the pathophysiology of haemolytic disease and collagen-induced arthritis. The intricate ways in which all three complement activation pathways correspond and modulate inflammatory conditions requires a more detailed understanding to open new therapeutic avenues in the treatment of inflammatory disease.

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Session 2: Complement dysregulation drives inflammation

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Complement dysregulation in C3 glomerulopathy

Professor Matthew Pickering

Abstract

Complement is an integral component of immunity. Inherited deficiencies in the ability to activate complement increase susceptibility to bacterial infection and autoimmunity. Inherited deficiencies in the ability to control complement activation result in damage to host tissue. Examples include red cell lysis in paroxysmal nocturnal haemoglobinuria, glomerular thrombosis in atypical haemolytic uraemic syndrome and glomerular inflammation in C3 glomerulopathy. In this presentation I will review the association between complement dysregulation and C3 glomerulopathy and discuss our current understanding of the mechanisms underlying these associations. I will outline how this can be applied to existing and novel treatment strategies together with how we should approach the management of C3 glomerulopathy in 2015.

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Targeting mechanisms at sites of complement activation for imaging and therapy

Professor V. Michael Holers MD

Abstract

The complement system plays a key role in many acute injury states as well as chronic autoimmune and inflammatory diseases. Despite this understanding, many of the mechanisms that underlie site-specific complement activation and amplification are poorly understood. In addition, there is only a limited capability to measure the level of local tissue-specific complement activation in patients without performing biopsies. This presentation will review emerging evidence that pro-inflammatory natural antibodies, effector pathway-catalyzed amplification processes, and components of the lectin pathway play key roles in amplification of complement-dependent injury. In addition, an imaging strategy designed to quantitatively measure local complement C3 fixation will be reviewed. Several of these findings and approaches have relevance to therapeutic strategies targeting the complement system.

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Complement genetics and susceptibility to inflammatory disease

Professor Santiago Rodriguez de Cordoba

Abstract

Different genome-wide linkage and association studies performed during the last 15 years have associated mutations and polymorphisms in complement genes with different diseases characterized by tissue damage and inflammation. These are complex disorders in which genetically susceptible individuals usually develop the pathology as a consequence of environmental triggers. Despite complement dysregulation is a common feature of these pathologies, how the disease phenotype is determined is only partly understood. To advance this understanding we have focused our research in the analysis of the peculiar genotype-phenotype correlations that characterize some of these diseases. Understanding the functional consequences of these disease-associated complement genetic variants is providing us with novel insights into the complement biology and a better knowledge of the pathogenic mechanisms underlying each of these pathologies. These advances have important therapeutic and diagnostic implications.

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Target discovery in the kidney transplant

Professor Steven Sacks FMedSci

Abstract

Focus on the cellular sources of complement in renal transplantation has brought into vision two new pathways of complement-mediated injury. Both require extravascular synthesis and activation of the principal complement component C3 and the downstream release of complement effectors that induce tissue parenchymal injury or provoke cellular immune responses. Knowledge of these mechanisms has contributed to the design of a new class of protein implant that inhibits the activation of C3 and protects the donor kidney from complement-mediated injury once the organ has been transplanted. Despite these advances, we are still short of understanding what biochemical aberrations in the donor organ trigger the complement cascade and hence are denied the opportunity for more selective interventions upstream of C3. The recent discovery of collectin 11 and its major epithelial site of expression within the kidney is a game-changer, since collectin 11 is able to spark the lectin pathway of complement at vulnerable tissue sites. This provides a challenge to design selective inhibitors that block collectin 11 from interacting with its preferred ligands and thus leave intact the collectin 11-independent functions of complement.

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Session 3: Strategies for inhibition

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Aiming at the center: therapeutic intervention of complement-mediated diseases at the level of C3

Dr Daniel Ricklin

Abstract

The plasma protein C3 acts as a central functional hub that largely drives activation, amplification and effector generation of the complement response. Insufficient control of C3 activation has long been recognized as a contributing force in many inflammatory, immune and age-related diseases. Pharmacological modulation of C3 activation may therefore offer a unique opportunity to interfere with or even prevent complement-driven pathologies at a central stage. While no C3-targed inhibitors have so far been approved for clinical use, several promising concepts have been introduced in recent years. This presentation highlights current therapeutic strategies to control C3 activation in preclinical development and clinical trials, provides examples of promising indications, and discusses chances and challenges on the road to bringing C3-targeted therapeutics to the clinic.

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Targeting C5a and neutrophil activation

Professor Markus Huber-Lang

Abstract

The complement activation product C5a interacts with neutrophils as “first line of defence” in a Janus face manner. It is well established that both C5a and neutrophils play an important role in the early development of systemic inflammatory response syndrome (SIRS) after trauma and during sepsis. Therefore, C5a represents a promising target for therapeutic interventions to improve cellular and organ functions. In experimental sepsis blockade of the C5a-C5aR-interaction revealed significant protective effects even when applied 12 h after the onset of sepsis. The underlying mechanisms include improvement of various neutrophil functions (such as danger sensing, chemotaxis, phagocytosis, oxidative burst), the coagulation system and multiple organ functions. In the clinical setting, loss of C5aR and C5L2-expression on neutrophils from severely ill patients on the ICU is associated with development of infectious complications, multi-organ failure and poor outcome.  As a novel therapeutic strategy, a “double-blockade” of both, the complement system (on the C5 level) and the toll-like-receptors (on the CD14 level) has been found to be more effective than the single treatments. Thus, targeting C5a with modulation of the subsequent cellular response seems a reasonable translational approach to improve clinical outcome after severe tissue injury and during sepsis.

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Structure-guided drug design

Professor Susan M. Lea

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Antisense therapies targeting complement in renal disease

Dr Tamar Grossman

Abstract

Activation of the complement system plays a key role in normal inflammatory response to injury but may cause substantial injury when activated inappropriately. Complement contributes to injury in several forms of glomerulonephritis, in acute and chronic humoral rejection after renal transplantation, and lupus nephritis. We identified and characterized antisense oligonucleotides (ASO) targeting complement component 5 (C5), complement factor B (FB) or complement factor D (FD) and tested the efficacy of these 3 inhibitors in murine renal disease models. Systemic Treatment with FB, FD or C5 ASOs to MRL/lpr mice resulted in a robust knockdown of the target genes, improved proteinuria, reduced renal C3 accumulation and improved renal pathology. Our results suggest that FB, FD and C5 play important roles in disease progression and pathology. Treatment with ASO to FB, FD or C5 may offer a novel treatment strategy to lupus nephritis and other complement related renal diseases.

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Session 4: Clinical trials of complement inhibition

3 talks Show detail Hide detail

Targeting the alternative complement pathway in age-related macular degeneration

Dr Menno van Lookeren Campagne

Abstract

Age-related macular degeneration (AMD) is a leading cause of blindness in individuals 55 years and older. In addition, Geographic Atrophy (GA), the advanced form of dry AMD, has no approved treatments representing a significant unmet medical need. Recent studies have implicated the alternative complement pathway in the pathogenesis of AMD, including polymorphisms in genes coding for proteins in the alternative complement pathway.

Complement factor D (CFD) is a rate-limiting enzyme in the alternative pathway and was pursued as a therapeutic target for GA. In the MAHALO phase II clinical study, monthly administration of a monoclonal antibody fragment (lampalizumab) that inhibits human CFD showed a 44% reduction in GA area progression at month 18 in a subpopulation of patients that were positive for the complement factor I risk allele. Results from this study suggest that genetic variation may be used to identify pathways critical for GA lesion progression and treatment response.

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Clinical trials with membrane targeting complement inhibitors

Professor Richard A. Smith

Abstract

Cytotopic modification technology has been developed to confer cell binding properties on soluble peptides and proteins. This approach involves site-specific attachment of synthetic membrane-interactive peptides and enables a therapeutic strategy which involves perfusion or local administration of such agents to organs or cells. Retention of the agent on cell surfaces increases the therapeutic ratio and reduces systemic exposure. The critical involvement of the complement system in kidney disease and in the ischaemia-reperfusion injury associated with renal transplantation has led to a focus on using modified complement inhibitors (particularly the CR1-derived Mirococept) by perfusion of kidneys prior to transplantation. Animal studies have been translated to clinical application firstly through a Phase 1 study in healthy volunteers, secondly through a pilot Phase II study in human renal transplantation and thirdly through a large-scale dose-escalating Phase II transplantation study in which the primary endpoint is the reduction of delayed graft function. The design of this study (called EMPIRIKAL) will be described in detail.

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Patient stratification and therapy in aHUS

Professor Tim Goodship

Abstract

Approximately 50% of aHUS patients have an underlying inherited and/or acquired abnormality of complement which predisposes to excessive activation of the alternative pathway. Use of complement inhibitors such as eculizumab to treat aHUS is therefore logical. Anecdotal reports and subsequent open-label trials demonstrated the efficacy of eculizumab in aHUS leading to approval by both the FDA and EMA. NHS England established in 2013 an interim national service for aHUS including funding for eculizumab for both new patients and those undergoing transplantation. 79 aHUS patients in England have been treated with eculizumab under this commissioning policy. The investigation and response to treatment in this cohort provides a unique resource for patient stratification.

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Complement: driver of inflammation and therapeutic target in diverse diseases.

Theo Murphy international scientific meeting organised by Professor Paul Morgan FMedSci and Professor Sir Peter Lachmann FMedSci FRS

Kavli Royal Society Centre, Chicheley Hall Newport Pagnell Buckinghamshire MK16 9JJ
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