Current and Future Approaches for Monitoring Responses to Anti-complement Therapeutics

Mohebnasab, Maede; Eriksson, Oskar; Persson, Bo‐Eric; Sandholm, Kerstin; Mohlin, Camilla; Huber‐Lang, Markus; Keating, Brendan J.; Ekdahl, Kristina Nilsson; Nilsson, Bo

doi:10.3389/fimmu.2019.02539

Cited by 15 publications

(18 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therapeutic agents that target molecules in the complement activation cascade could arrest complement-mediated tissue damage, a possibility that has generated great interest and a series of ongoing clinical trials in several neurological disorders. Several anti-complement therapeutic strategies are possible: preventing initiation of the initial activation step; inhibiting convertase assembly or promoting convertase breakdown; and inhibiting C5 cleavage, thereby preventing C5a–C5aR1 interactions and intercepting formation of the MAC 145 , 146 . To date, targeting C5 cleavage has been the most successful strategy, and several emerging biologics have had remarkable benefits in difficult-to-treat autoimmune neurological diseases, leading to FDA approval for some.…”

Section: Complement-targeted Therapiesmentioning

confidence: 99%

Complement in neurological disorders and emerging complement-targeted therapeutics

2020

View full text Add to dashboard Cite

The human complement system is an effector of innate and adaptive humoral immunity. The system comprises soluble membrane-bound proteins (opsonins) that act collectively to recognize pathogens and non-self material and subsequently initiate opsonization and phagocytosis or lysis of pathogens. The proteolytic fragments that derive from complement activation can be targeted by white blood cells and endothelial cells, leading to extravasation and migration of immune cells at the sites of inflammation. Other physiological functions of complement include timely removal of altered and senescent self, tissue remodelling, cell lysis, chemotaxis, opsonization, inflammation and immune cell stimulation 1-4. Complement activation products link the innate and adaptive immune systems by acting directly on receptors on T cells and B cells or by modulating dendritic cell functions 5-8. Disruption of the delicate coordination required for complement activation and control is fundamental in the pathogenic mechanism of several autoimmune neurological disorders, and is even emerging as a contributor in some neurodegenerative diseases. As a result, interest is increasing in targeting complement as a therapeutic approach to prevent ongoing tissue destruction in several difficult-to-treat neurological diseases. In this Review, we provide an overview of the main components of the initial complement activation pathways, the lytic pathway and the factors associated with inappropriate complement activation or control in disease initiation and progression. We consider the role of complement in the tissue destruction that is responsible for the genesis of the most common autoimmune neurological diseases, including complement-mediated myopathies, myasthenia gravis, neuropathies and CNS disorders. We also discuss the role of complement in some neurodegenerative disorders, including Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), Huntington disease, traumatic brain injury and even schizophrenia. Finally, we discuss emerging complement-targeted therapies, such as monoclonal antibodies, fusion proteins and cyclic peptides, that inhibit the functions of individual complement proteins, especially therapies that disrupt the lytic pathway. Some of these therapeutic agents have been approved or are being tested in phase I-III clinical trials and promise to change the therapeutic armamentarium for treatment of neurological conditions that respond poorly to existing immunotherapies.

show abstract

Section: Complement-targeted Therapiesmentioning

confidence: 99%

Complement in neurological disorders and emerging complement-targeted therapeutics

2020

View full text Add to dashboard Cite

show abstract

“…Yet, measurement of sC5b-9 in blood or urine is cumbersome due to its easy formation in vitro and short half-life ( 34 ). Deposition of C5b-9 in kidneys is thought to better reflect the involvement of its formation in the pathogenesis of kidney diseases ( 35 , 36 ). The membrane-bound form may more accurately indicate complement activation and disease activity than its circulating soluble form, as has been shown for other complement factors in SLE ( 10 , 11 , 37 , 38 ).…”

Section: Introductionmentioning

confidence: 99%

Deposition of the Membrane Attack Complex in Healthy and Diseased Human Kidneys

et al. 2021

View full text Add to dashboard Cite

The membrane attack complex—also known as C5b-9—is the end-product of the classical, lectin, and alternative complement pathways. It is thought to play an important role in the pathogenesis of various kidney diseases by causing cellular injury and tissue inflammation, resulting in sclerosis and fibrosis. These deleterious effects are, consequently, targeted in the development of novel therapies that inhibit the formation of C5b-9, such as eculizumab. To clarify how C5b-9 contributes to kidney disease and to predict which patients benefit from such therapy, knowledge on deposition of C5b-9 in the kidney is essential. Because immunohistochemical staining of C5b-9 has not been routinely conducted and never been compared across studies, we provide a review of studies on deposition of C5b-9 in healthy and diseased human kidneys. We describe techniques to stain deposits and compare the occurrence of deposits in healthy kidneys and in a wide spectrum of kidney diseases, including hypertensive nephropathy, diabetic nephropathy, membranous nephropathy, IgA nephropathy, lupus nephritis, C3 glomerulopathy, and thrombotic microangiopathies such as the atypical hemolytic uremic syndrome, vasculitis, interstitial nephritis, acute tubular necrosis, kidney tumors, and rejection of kidney transplants. We summarize how these deposits are related with other histological lesions and clinical characteristics. We evaluate the prognostic relevance of these deposits in the light of possible treatment with complement inhibitors.

show abstract

“…ImmunoTargets and Therapy 2020:9 64 Mohebnasab et al 65 Kerboua et al 70 Liu et al 71 Complement activation products C3a, C5a, sC5b9…”

Section: Dovepressmentioning

confidence: 99%

“…Recently, multiplex assays have been developed with the advantage of simultaneously determine more complement proteins in one sample, providing a comprehensive complement component profile. In addition, quantification of products generated during complement activation, including C3a, C5a, and soluble C5b9 (sC5b9 or sMAC), in properly collected serum/plasma samples, 70 can be used to monitor the degree of complement activation during the disease course. Complement activity functional tests, mainly consisting in hemolytic assays measuring classical (CH50) 71 and alternative (AH50) 72 pathways, from initiation to the effector phase (MAC formation), provide further information regarding the patient-specific complement activation status, and can be therefore useful to monitor complement function during disease exacerbations or crisis.…”

Section: Biomarkers For Tailoring and Monitoring Complement-targeted mentioning

confidence: 99%

See 1 more Smart Citation

<p>Complement Inhibition for the Treatment of Myasthenia Gravis</p>

Mantegazza

Vanoli

Frangiamore

et al. 2020

ITT

View full text Add to dashboard Cite

Generalized myasthenia gravis (gMG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Approximately 80–90% of patients display antibodies directed against the nicotinic acetylcholine receptor (AChR). A major drive of AChR antibody-positive MG pathology is represented by complement activation. The role of the complement cascade has been largely demonstrated in patients and in MG animal models. Complement activation at the NMJ leads to focal lysis of the post-synaptic membrane, disruption of the characteristic folds, and reduction of AChR. Given that the complement system works as an activation cascade, there are many potential targets that can be considered for therapeutic intervention. Preclinical studies have confirmed the efficacy of complement inhibition in ameliorating MG symptoms. Eculizumab, an antibody directed towards C5, has recently been approved for the treatment of AChR antibody-positive gMG. Other complement inhibitors, targeting C5 as well, are currently under phase III study. Complement inhibitors, however, may present prohibitive costs. Therefore, the identification of a subset of patients more or less prone to respond to such therapies would be beneficial. For such purpose, there is a critical need to identify possible biomarkers predictive of therapeutic response, a field not yet sufficiently explored in MG. This review aims to give an overview of the complement cascade involvement in MG, the evolution of complement-inhibiting therapies and possible biomarkers useful to tailor and monitor complement-directed therapies.

show abstract

Current and Future Approaches for Monitoring Responses to Anti-complement Therapeutics

Cited by 15 publications

References 50 publications

Complement in neurological disorders and emerging complement-targeted therapeutics

Complement in neurological disorders and emerging complement-targeted therapeutics

Deposition of the Membrane Attack Complex in Healthy and Diseased Human Kidneys

<p>Complement Inhibition for the Treatment of Myasthenia Gravis</p>

Contact Info

Product

Resources

About