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Article ; Online: XXIX International Complement Workshop Newcastle 2023.

Marchbank, Kevin J / Kavanagh, David / Harris, Claire L

2023 Volume 228, Issue 5, Page(s) 152729

Language	English
Publishing date	2023-08-10
Publishing country	Netherlands
Document type	Editorial
ZDB-ID	563292-4
ISSN	1878-3279 ; 0171-2985
ISSN (online)	1878-3279
ISSN	0171-2985
DOI	10.1016/j.imbio.2023.152729
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Article ; Online: Expanding horizons in complement drug discovery: challenges and emerging strategies.

Harris, Claire L

Seminars in immunopathology

2017 Volume 40, Issue 1, Page(s) 125–140

Abstract: The complement system is best known for its role in innate immunity, providing a first line of defence against infection, maintaining tissue homeostasis by flagging apoptotic cells and debris for removal, and orchestrating crosstalk between adaptive and ... ...

Abstract	The complement system is best known for its role in innate immunity, providing a first line of defence against infection, maintaining tissue homeostasis by flagging apoptotic cells and debris for removal, and orchestrating crosstalk between adaptive and innate immunity. In a growing number of diseases, complement is known to drive pathogenesis or to contribute as an inflammatory amplifier of a disease trigger. Association of complement with common and devastating diseases has driven an upsurge in complement drug discovery, but despite a wealth of knowledge in the complexities of the cascade, and many decades of effort, very few drugs have progressed to late-stage clinical studies. The reasons for this are becoming clear with difficulties including high target concentration and turnover, lack of clarity around disease mechanism and unwanted side effects. Lessons learnt from drugs which are either approved, or are currently in late-stage development, or have failed and dropped off the drug development landscape, have been invaluable to drive a new generation of innovative drugs which are progressing through clinical development. In this review, the challenges associated with complement drug discovery are discussed and the current drug development landscape is reviewed. The latest approaches to improve drug characteristics are explored and those agents which employ these technologies to improve accessibility to patients are highlighted.
MeSH term(s)	Animals ; Complement Activation/drug effects ; Complement Activation/immunology ; Complement System Proteins/immunology ; Disease Susceptibility/immunology ; Drug Design ; Drug Discovery/methods ; Epitopes/immunology ; Humans ; Molecular Targeted Therapy ; Protein Engineering ; Structure-Activity Relationship
Chemical Substances	Epitopes ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2017-10-06
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	2316828-6
ISSN	1863-2300 ; 1863-2297
ISSN (online)	1863-2300
ISSN	1863-2297
DOI	10.1007/s00281-017-0655-8
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Article ; Online: The complement alternative pathway in health and disease-activation or amplification?

Harrison, Richard A / Harris, Claire L / Thurman, Joshua M

Immunological reviews

2022 Volume 313, Issue 1, Page(s) 6–14

MeSH term(s)	Humans ; Complement Activation ; Complement Pathway, Alternative ; Complement System Proteins
Chemical Substances	Complement System Proteins (9007-36-7)
Language	English
Publishing date	2022-11-24
Publishing country	England
Document type	Journal Article
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.13172
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Article ; Online: The case for complement component 5 as a target in neurodegenerative disease.

Stennett, Amelia / Friston, Kallie / Harris, Claire L / Wollman, Adam J M / Bronowska, Agnieszka K / Madden, Katrina S

Expert opinion on therapeutic targets

2023 Volume 27, Issue 2, Page(s) 97–109

Abstract: Introduction: Complement-based drug discovery is undergoing a renaissance, empowered by new advances in structural biology, complement biology and drug development. Certain components of the complement pathway, particularly C1q and C3, have been ... ...

Abstract	Introduction: Complement-based drug discovery is undergoing a renaissance, empowered by new advances in structural biology, complement biology and drug development. Certain components of the complement pathway, particularly C1q and C3, have been extensively studied in the context of neurodegenerative disease, and established as key therapeutic targets. C5 also has huge therapeutic potential in this arena, with its druggability clearly demonstrated by the success of C5-inhibitor eculizumab. Areas covered: We will discuss the evidence supporting C5 as a target in neurodegenerative disease, along with the current progress in developing different classes of C5 inhibitors and the gaps in knowledge that will help progress in the field. Expert opinion: Validation of C5 as a therapeutic target for neurodegenerative disease would represent a major step forward for complement therapeutics research and has the potential to furnish disease-modifying drugs for millions of patients suffering worldwide. Key hurdles that need to be overcome for this to be achieved are understanding how C5a and C5b should be targeted to bring therapeutic benefit and demonstrating the ability to target C5 without creating vulnerability to infection in patients. This requires greater biological elucidation of its precise role in disease pathogenesis, supported by better chemical/biological tools.
MeSH term(s)	Humans ; Complement C5/metabolism ; Neurodegenerative Diseases/drug therapy ; Complement Activation ; Complement C5a
Chemical Substances	Complement C5 ; Complement C5a (80295-54-1)
Language	English
Publishing date	2023-02-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2055208-7
ISSN	1744-7631 ; 1472-8222
ISSN (online)	1744-7631
ISSN	1472-8222
DOI	10.1080/14728222.2023.2177532
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Article ; Online: Gene targeting as a therapeutic avenue in diseases mediated by the complement alternative pathway

Dreismann, Anna K / Hallam, Thomas M / Tam, Lawrence CS / Nguyen, Calvin V / Hughes, Jane P / Ellis, Scott / Harris, Claire L.

Immunological Reviews 2023 Jan., v. 313, no. 1, p. 402-419

2023 , Page(s) 402–419

Abstract: The complement alternative pathway (AP) is implicated in numerous diseases affecting many organs, ranging from the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH), to the common blinding disease age‐related macular degeneration (AMD). ...

Abstract	The complement alternative pathway (AP) is implicated in numerous diseases affecting many organs, ranging from the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH), to the common blinding disease age‐related macular degeneration (AMD). Critically, the AP amplifies any activating trigger driving a downstream inflammatory response; thus, components of the pathway have become targets for drugs of varying modality. Recent validation from clinical trials using drug modalities such as inhibitory antibodies has paved the path for gene targeting of the AP or downstream effectors. Gene targeting in the complement field currently focuses on supplementation or suppression of complement regulators in AMD and PNH, largely because the eye and liver are highly amenable to drug delivery through local (eye) or systemic (liver) routes. Targeting the liver could facilitate treatment of numerous diseases as this organ generates most of the systemic complement pool. This review explains key concepts of RNA and DNA targeting and discusses assets in clinical development for the treatment of diseases driven by the alternative pathway, including the RNA‐targeting therapeutics ALN‐CC5, ARO‐C3, and IONIS‐FB‐LRX, and the gene therapies GT005 and HMR59. These therapies are but the spearhead of potential drug candidates that might revolutionize the field in coming years.
Keywords	DNA ; RNA ; complement ; drugs ; eyes ; genes ; hemoglobinuria ; inflammation ; liver ; macular degeneration ; therapeutics
Language	English
Dates of publication	2023-01
Size	p. 402-419.
Publishing place	John Wiley & Sons, Inc
Document type	Article ; Online
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.13149
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Article ; Online: Extracting the barbs from complement assays: Identification and optimisation of a safe substitute for traditional buffers.

Zelek, Wioleta M / Harris, Claire L / Morgan, B Paul

Immunobiology

2018 Volume 223, Issue 12, Page(s) 744–749

Abstract: Complement assays have for many years utilised buffers based on barbitone (veronal) despite the well-recognised toxicity of this agent and the tight regulations on its use in most countries. The use of barbitone in complement assay buffers is steeped in ... ...

Abstract	Complement assays have for many years utilised buffers based on barbitone (veronal) despite the well-recognised toxicity of this agent and the tight regulations on its use in most countries. The use of barbitone in complement assay buffers is steeped in history, from a time when no other suitable buffers were available. This is no longer the case, encouraging us to explore alternatives to barbitone for complement assays. We compared a simple, non-toxic HEPES buffer with commercially sourced complement fixation test diluent (CFD), the "gold standard" barbitone buffer, in several clinically relevant complement activity assays and across species. In classical pathway haemolysis assays in human and non-human serum, there was no difference in haemolytic curves or calculated haemolytic activity (CH50) between CFD and an optimised HEPES buffer (HBS) supplemented with cations. Alternative pathway haemolysis assays in human serum were also identical in the two buffers. In a complement fixation test for anti-erythrocyte antibodies, complement consumption was identical for the two buffer systems. The data demonstrate that barbitone-based buffers are unnecessary for assays of complement activity and can readily be replaced with safe and simple alternatives.
MeSH term(s)	Animals ; Buffers ; Complement Activation/immunology ; Complement System Proteins/immunology ; Erythrocytes/immunology ; Guinea Pigs ; Hemolysis/immunology ; Humans ; Immunoassay/methods ; Mice ; Rats
Chemical Substances	Buffers ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2018-07-20
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	563292-4
ISSN	1878-3279 ; 0171-2985
ISSN (online)	1878-3279
ISSN	0171-2985
DOI	10.1016/j.imbio.2018.07.016
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Article ; Online: Complement, a target for therapy in inflammatory and degenerative diseases.

Morgan, B Paul / Harris, Claire L

Nature reviews. Drug discovery

2015 Volume 14, Issue 12, Page(s) 857–877

Abstract: The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled activation of complement can cause local and/or systemic ... ...

Abstract	The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. In this Review, we describe the history, current landscape and future directions for anti-complement therapies.
MeSH term(s)	Clinical Trials as Topic ; Complement Activation/drug effects ; Complement Activation/immunology ; Complement Inactivating Agents/immunology ; Complement Inactivating Agents/pharmacology ; Complement System Proteins/immunology ; Humans ; Inflammation/drug therapy ; Inflammation/immunology
Chemical Substances	Complement Inactivating Agents ; Complement System Proteins (9007-36-7)
Keywords	covid19
Language	English
Publishing date	2015-10-23
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2062954-0
ISSN	1474-1784 ; 1474-1776
ISSN (online)	1474-1784
ISSN	1474-1776
DOI	10.1038/nrd4657
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Article ; Online: Gene targeting as a therapeutic avenue in diseases mediated by the complement alternative pathway.

Dreismann, Anna K / Hallam, Thomas M / Tam, Lawrence Cs / Nguyen, Calvin V / Hughes, Jane P / Ellis, Scott / Harris, Claire L

Immunological reviews

2022 Volume 313, Issue 1, Page(s) 402–419

Abstract	The complement alternative pathway (AP) is implicated in numerous diseases affecting many organs, ranging from the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH), to the common blinding disease age-related macular degeneration (AMD). Critically, the AP amplifies any activating trigger driving a downstream inflammatory response; thus, components of the pathway have become targets for drugs of varying modality. Recent validation from clinical trials using drug modalities such as inhibitory antibodies has paved the path for gene targeting of the AP or downstream effectors. Gene targeting in the complement field currently focuses on supplementation or suppression of complement regulators in AMD and PNH, largely because the eye and liver are highly amenable to drug delivery through local (eye) or systemic (liver) routes. Targeting the liver could facilitate treatment of numerous diseases as this organ generates most of the systemic complement pool. This review explains key concepts of RNA and DNA targeting and discusses assets in clinical development for the treatment of diseases driven by the alternative pathway, including the RNA-targeting therapeutics ALN-CC5, ARO-C3, and IONIS-FB-LRX, and the gene therapies GT005 and HMR59. These therapies are but the spearhead of potential drug candidates that might revolutionize the field in coming years.
MeSH term(s)	Humans ; Complement System Proteins/genetics ; Complement System Proteins/metabolism ; Hemoglobinuria, Paroxysmal/drug therapy ; Hemoglobinuria, Paroxysmal/genetics ; Gene Targeting ; Complement Pathway, Alternative
Chemical Substances	Complement System Proteins (9007-36-7)
Language	English
Publishing date	2022-11-12
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.13149
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Article ; Online: Compendium of current complement therapeutics.

Zelek, Wioleta M / Xie, Long / Morgan, B Paul / Harris, Claire L

Molecular immunology

2019 Volume 114, Page(s) 341–352

Abstract: The complement system is well known for its role in innate immunity and in maintenance of tissue homeostasis, providing a first line of defence against infection and playing a key role in flagging apoptotic cells and debris for disposal. Unfortunately, ... ...

Abstract	The complement system is well known for its role in innate immunity and in maintenance of tissue homeostasis, providing a first line of defence against infection and playing a key role in flagging apoptotic cells and debris for disposal. Unfortunately, complement also contributes to pathogenesis of many diseases, in some cases driving pathology, and in others amplifying or exacerbating the inflammatory and damaging impact of non-complement disease triggers. The driving role of complement in a single disease, paroxysmal nocturnal hemoglobinuria (PNH), provoked the development and eventual FDA (US Food and Drug Administration) approval of eculizumab (Soliris™), an anti-C5 antibody, for therapy. Although PNH is very rare, eculizumab provided clinical validation and demonstrated that inhibiting the complement system was not only well-tolerated, but also provided rapid therapy and saved lives. This clinical validation, together with advances in genetic analyses that demonstrated strong associations between complement and common diseases, drove new drug discovery programmes in both academic laboratories and large pharmaceutical companies. Numerous drugs have entered clinical development and several are in phase 3 trials; however, many have fallen by the wayside. Despite this high attrition rate, crucial lessons have been learnt and hurdles to development have become clear. These insights have driven development of next generation anti-complement drugs designed to avoid pitfalls and facilitate patient access. In this article, we do not set out to provide a text-heavy review of complement therapeutics but instead will simply highlight the targets, modalities and current status of the plethora of drugs approved or in clinical development. With such a fast-moving drug development landscape, such a compendium will inevitably become out-dated; however, we provide a snapshot of the current field and illustrate the increased choice that clinicians might enjoy in the future in selecting the best drug for their application, decisions based not only on efficacy but also cost, mechanistic target, modality and route of delivery.
MeSH term(s)	Antibodies/immunology ; Antibodies, Monoclonal, Humanized/immunology ; Clinical Trials, Phase III as Topic ; Complement Activation/immunology ; Complement C5/immunology ; Drug Discovery/methods ; Hemoglobinuria, Paroxysmal/immunology ; Humans
Chemical Substances	Antibodies ; Antibodies, Monoclonal, Humanized ; Complement C5 ; eculizumab (A3ULP0F556)
Language	English
Publishing date	2019-08-22
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	424427-8
ISSN	1872-9142 ; 0161-5890
ISSN (online)	1872-9142
ISSN	0161-5890
DOI	10.1016/j.molimm.2019.07.030
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Article ; Online: Revisiting the role of factor H in age-related macular degeneration: Insights from complement-mediated renal disease and rare genetic variants.

Tzoumas, Nikolaos / Hallam, Dean / Harris, Claire L / Lako, Majlinda / Kavanagh, David / Steel, David H W

Survey of ophthalmology

2020 Volume 66, Issue 2, Page(s) 378–401

Abstract: Ophthalmologists are long familiar with the eye showing signs of systemic disease, but the association between age-related macular degeneration and abnormal complement activation, common to several renal disorders, has only recently been elucidated. ... ...

Abstract	Ophthalmologists are long familiar with the eye showing signs of systemic disease, but the association between age-related macular degeneration and abnormal complement activation, common to several renal disorders, has only recently been elucidated. Although complement activation products were identified in drusen almost three decades ago, it was not until the early 21st century that a single-nucleotide polymorphism in the complement factor H gene was identified as a major heritable determinant of age-related macular degeneration, galvanizing global efforts to unravel the pathogenesis of this common disease. Advances in proteomic analyses and familial aggregation studies have revealed distinctive clinical phenotypes segregated by the functional effects of common and rare genetic variants on the mature protein and its splice variant, factor H-like protein 1. The predominance of loss-of-function, N-terminal mutations implicate age-related macular degeneration as a disease of general complement dysregulation, offering several therapeutic avenues for its modulation. Here, we explore the molecular impact of these mutations/polymorphisms on the ability of variant factor H/factor H-like protein 1 to localize to polyanions, pentraxins, proinflammatory triggers, and cell surfaces across ocular and renal tissues and exert its multimodal regulatory functions and their clinical implications. Finally, we critically evaluate key therapeutic and diagnostic efforts in this rapidly evolving field.
MeSH term(s)	Complement Factor H/genetics ; Complement Factor H/metabolism ; Complement System Proteins/genetics ; Humans ; Macular Degeneration/genetics ; Phenotype ; Proteomics
Chemical Substances	CFH protein, human ; Complement Factor H (80295-65-4) ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2020-11-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	391346-6
ISSN	1879-3304 ; 0039-6257
ISSN (online)	1879-3304
ISSN	0039-6257
DOI	10.1016/j.survophthal.2020.10.008
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