TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins

Shi, Ju; Rose, Eileen L.; Singh, Andrew; Hussain, Sami; Stagliano, Nancy E.; Parry, Graham; Panicker, Sandip

doi:10.1182/blood-2014-02-556027

Cited by 129 publications

(163 citation statements)

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“…TNT003 also efficiently reduced the generation of proinflammatory and vasoactive anaphylatoxins. 33 Moreover, TNT003 efficiently inhibited cold-agglutinin-mediated RBC hemolysis. In a humanized form, TNT003 might be a suitable inhibitor to block complement-mediated RBC destruction in AIHA.…”

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“…In a humanized form, TNT003 might be a suitable inhibitor to block complement-mediated RBC destruction in AIHA. 33 Recently, TNT003 was successfully tested in an in vitro model for antibody-mediated graft rejection (AMR) showing its potency to reduce antibody-mediated classical pathway activation. 67 In addition, plasma-derived C1-inh is currently being tested in clinical trials for its efficacy in preventing AMR in kidney transplantation (clincialtrials.gov identifier: 01147302 and 01134510).…”

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confidence: 99%

“…Recently two studies have been published in which inhibitors of the CP were shown to inhibit in vitro complement activation on antibody-sensitized RBCs. 33,65 In the first study, supraphysiological levels of an endogenous plasma inhibitor of the CP, C1-inh, were used. 65 Red blood cells that were in vitro opsonized with patient antibodies were protected from C3 deposition and hemolysis upon co-incubation with high levels of C1-inh.…”

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Complement inhibitors to treat IgM-mediated autoimmune hemolysis

Wouters

2015

Haematologica

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© 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...

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Complement inhibitors to treat IgM-mediated autoimmune hemolysis

Wouters

2015

Haematologica

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“…Shi, et al Recently showed that a novel serine protease C1s inhibitor could inhibit complement activation by cold agglutinins, the main mechanism of haemolysis in cold agglutinin disease [32]. If flares are unable to be prevented, general anticoagulation may be considered.…”

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Autoimmune Hemolytic Anemia Confers an Independent Risk Factor for Thrombosis: Retrospective Cohort Study Using the “STRIDE” Database

Kummar¹

2017

Ann Hematol Oncol

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“…I tillegg pågår studier innenfor så varierte områder som sepsis, obstruktiv lungesykdom, inflammatorisk tarmsykdom og ulike former for iskemireperfusjonsskade (5). Også ved noen former for autoimmun hemolytisk anemi og ved akutte hemolytiske transfusjonsreaksjoner er det mulig at komplementhemming kan ha en plass (26,27).…”

Section: Mulige Fremtidige Indikasjonerunclassified