A novel approach to preventing the hemolysis of paroxysmal nocturnal hemoglobinuria: both complement-mediated cytolysis and C3 deposition are blocked by a monoclonal antibody specific for the alternative pathway of complement

Lindorfer, Margaret A.; Pawluczkowycz, Andrew W.; Peek, Elizabeth M.; Hickman, Kimberly; Taylor, Ronald P.; Parker, Charles J.

doi:10.1182/blood-2009-09-244285

Cited by 67 publications

(60 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nonetheless, continued investigation of new approaches to therapy aimed at obviating the extravascular hemolysis that limits eculizumab efficacy in some patients is warranted. 4 A better understanding of the pathobiology that underlies the thrombophilia of PNH is needed, and defining the complex relationship between PNH and BM failure syndromes that determine clonal selection and clonal expansion 40 may lead ultimately to therapy that targets the disease at the level of the hematopoietic stem cell. In particular, an understanding of the molecular basis of clonal expansion will be facilitated by the availability of next-generation sequencing that will allow comparison between the genomes of GPI-AP-positive and GPI-AP-negative cells from individual patients with PNH.…”

Section: Discussionmentioning

confidence: 99%

“…3 Unlike the classical complement pathway that is part of the system of acquired immunity and requires antibody for initiation of activation, the APC is in a state of continuous activation, armed always to protect the host. 4 The APC cascade can be divided into 2 functional components, the amplification C3 and C5 convertases and the cytolytic membrane attack complex (MAC) (Figure 1). The C3 and C5 convertases are enzymatic complexes that initiate and amplify the activity of the APC and ultimately generate the MAC.…”

Section: Pnh and Complementmentioning

confidence: 99%

“…By inhibiting the formation of the MAC, eculizumab prevents direct cytolysis of PNH erythrocytes, allowing the manifestations of DAF deficiency to become apparent in the form of aberrant regulation of the APC C3 convertase and the consequent deposition of activated C3 on the cell surface (Figures 1 and 4). 4 Covalently bound activation and degradation products of C3 then serve as opsonins that are recognized by specific receptors on reticuloendothelial cells, resulting in extravascular hemolysis ( Figure 4). …”

Section: Reasons For Suboptimal Response To Treatment With Eculizumabmentioning

confidence: 99%

See 2 more Smart Citations

Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy

Parker

2011

Hematology

Self Cite

View full text Add to dashboard Cite

Despite the availability of safe, effective targeted therapy that controls intravascular hemolysis, the management of paroxysmal nocturnal hemoglobinuria (PNH) remains complicated because of disease heterogeneity and close association with BM failure syndromes. The purpose of this review is to provide a framework for individualizing treatment based on disease classification. According to the recommendations of the International PNH Interest Group, patients can be placed into one of the following 3 categories: (1) classic PNH, (2) PNH in the setting of another BM failure syndrome, or (3) subclinical PNH. The PNH clone in patients with subclinical disease is insufficiently large to produce even biochemical evidence of hemolysis, and consequently, patients who fit into this category require no PNH-specific therapy. Patients with PNH in the setting of another BM failure syndrome (usually aplastic anemia or low-risk myelodysplastic syndrome) have at least biochemical evidence of hemolysis, but typically the PNH clone is small (Ͻ 10%) so that hemolysis does not contribute significantly to the underlying anemia. In these cases, the focus of treatment is on the BM failure component of the disease. Intravascular hemolysis is the dominant feature of classic PNH, and this process is blocked by the complement inhibitor eculizumab. The thrombophilia of PNH also appears to be ameliorated by eculizumab, but the drug has no effect on the BM failure component of the disease. Low-grade extravascular hemolysis due to complement C3 opsonization develops in most patients treated with eculizumab, and in some cases is a cause for suboptimal response to treatment. Allogeneic BM transplantation can cure classic PNH, but treatment-related toxicity suggests caution for this approach to management.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Pnh and Complementmentioning

confidence: 99%

Section: Reasons For Suboptimal Response To Treatment With Eculizumabmentioning

confidence: 99%

See 1 more Smart Citation

Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy

Parker

2011

Hematology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The Parker group reported monoclonal antibody H17/3E7 directed to C3b/C3bi, which efficiently inhibited hemolysis of RBCs from PNH patients. 52 Monoclonal H17/3E7 binds to C3(H 2 O) and C3b, thereby preventing C3-as well as C5-convertase formation resulting in efficient inhibition of the alternative pathway leaving classical pathway activation unaffected. Therefore, H17/3E7 efficiently inhibits both, hemolysis and C3 deposition on PNH RBCs in vitro.…”

mentioning

confidence: 99%

“…54 The FH SCR1-5 domains of the fusion protein efficiently prevent C3 convertase formation of the alternative pathway by its decay accelerating activity. 52,53 The efficacy of TT30 to inhibit alternative pathway activation at the site of complement activation has been demonstrated in haematologica | 2015; 100 (11) © F e r r a t a S t o r t i F o u n d a t i o n vitro in a hemolysis assay using rabbit RBCs. 53 Risitano and co-workers reported TT30 to efficiently inhibit C3 deposition on and hemolysis of PNH RBCs.…”

mentioning

confidence: 99%

Complement inhibitors to treat IgM-mediated autoimmune hemolysis

Wouters

2015

Haematologica

View full text Add to dashboard Cite

© F e r r a t a S t o r t i F o u n d a t i o n Complement systemThe complement system is an evolutionary highly conserved cascade system that makes up part of the innate immune system. [7][8][9] Complement activation can occur via three distinct pathways (classical pathway (CP), lectin pathway (LP) and alternative pathway (AP) that converge at the level of C3 cleavage and eventually lead to a common terminal pathway (TP) ( Figure 1A).The AP can be initiated by spontaneous hydrolysis of the central complement component into C3b(H 2 O). C3b(H 2 O) is an acceptor for the next AP protein Factor B (FB) which is then cleaved by the serine protease factor D (FD), resulting Complement inhibition in AIHA haematologica | 2015; 100 (11) 1389 The lectin pathway is initiated by binding of MBL (or ficolins) to sugar structures followed by activation of C2 and C4 by MASP1/MASP2, leading to the formation of lectin C3 convertase (C2aC4b). (E) C3-activation by the classical, lectin or alternative C3 convertase results in the formation of the C5 convertase. C5 convertase subsequently activates C5 resulting in the formation of the membrane attack complex (MAC). C: complement factor; MAC: membrane attack complex; MBL: mannan binding lectin; MASP: MBL-associated serine protease; P: properdin; C1-inh: C1-inhibitor; FI: factor I; CR1: complement receptor 1; MCP: membrane co-factor protein; DAF: decay accelerating factor; C4BP: C4-binding protein; FH: factor H. A B C D E © F e r r a t a S t o r t i F o u n d a t i o nin the fluid phase C3 convertase (C3b(H 2 O)Bb), that can cleave multiple C3 molecules into C3b and C3a. C3b binds to nucleophilic targets on cell membranes 10 and C3a acts as a pro-inflammatory anaphylatoxin ( Figure 1B). Low-level activation of C3 can significantly be accelerated through a positive feedback loop resulting in the formation of additional alternative C3 convertases on the surface (C3bBb) that are stabilized by properdin (P) and eventually give rise to the formation of a C5 convertase (C3bBbC3b), which subsequently cleaves C5 into C5b and C5a.10 C5b attaches to the surface and subsequently binds to C6, C7 and C8 to form the C5bC8 complex allowing polymerization of C9 to form the membrane attack complex (MAC), which inserts into target membranes and induces cell lysis ( Figure 1A and E). 11,12 Next to lysis by the MAC, cleavage of both C3 and C5 results in the generation of pro-inflammatory anaphylatoxins (C3a, C5a) that attract and activate leukocytes 13 and C3b opsonization of the target surface facilitates uptake by phagocytic cells in the liver and spleen.During evolution complement activation became more specific by the development of recognition molecules. The CP is initiated by binding of C1q to the Fc-part of IgM or IgG complexed with their target antigens. IgM is most efficient in complement activation, due to its polymeric nature. Human IgG activates complement in the order IgG3>IgG1>IgG2, whereas IgG4 does not activate complement at all.14 As the affinity of C1q for a single IgG Fc tail is...

show abstract

Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria

Martí‐Carvajal

Anand

Cardona

et al. 2013

Cochrane Database of Systematic Reviews

View full text Add to dashboard Cite

A novel approach to preventing the hemolysis of paroxysmal nocturnal hemoglobinuria: both complement-mediated cytolysis and C3 deposition are blocked by a monoclonal antibody specific for the alternative pathway of complement

Abstract: A novel approach to preventing the hemolysis of paroxysmal nocturnal hemoglobinuria: both complement-mediated cytolysis and C3 deposition are blocked by a monoclonal antibody specific for the alternative pathway of complement

Cited by 67 publications

References 39 publications

Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy

Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy

Complement inhibitors to treat IgM-mediated autoimmune hemolysis

Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria

Contact Info

Product

Resources

About