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Therapeutic control of complement activation at the level of the central component C3.

ABSTRACT: The increasing recognition of the complement system's association with diseases of the inflammatory spectrum and with biomaterial and transplant-related complications has generated growing interest in the therapeutic modulation of this innate immune cascade. As a central functional hub that largely drives the activation, amplification, and effector generation of the complement response, the plasma protein C3 has long been recognized as an attractive target. While pharmacological modulation of C3 activation may offer a powerful opportunity to interfere with or even prevent complement-driven pathologies, the development of C3 inhibitors has often been accompanied by concerns regarding the safety and feasibility of this approach. Although no C3-targeted inhibitors have thus far been approved for clinical use, several promising concepts and candidates have emerged in recent years. At the same time, experiences from preclinical development and clinical trials are slowly providing a more detailed picture of therapeutic complement inhibition at the level of C3. This review highlights the current therapeutic strategies to control C3 activation and discusses the possibilities and challenges on the road to bringing C3-targeted therapeutics to the clinic.

SUBMITTER: Ricklin D

PROVIDER: S-EPMC4675703 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Therapeutic control of complement activation at the level of the central component C3.

Ricklin Daniel D Lambris John D JD

Immunobiology 20150610 6

The increasing recognition of the complement system's association with diseases of the inflammatory spectrum and with biomaterial and transplant-related complications has generated growing interest in the therapeutic modulation of this innate immune cascade. As a central functional hub that largely drives the activation, amplification, and effector generation of the complement response, the plasma protein C3 has long been recognized as an attractive target. While pharmacological modulation of C3 ...[more]

PMID: 26101137

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Project description:We aimed at establishing a sensitive and robust assay for estimation of systemic complement activation at complement component C3 level in mouse and human plasma samples. In order to capture the activation products iC3b and C3dg in a specific and physiological relevant manner we utilized a construct consisting of the iC3b/C3dg-binding site of human complement receptor 2 (CR2) attached to an Fc-part of mouse IgG. This construct binds C3dg and iC3b from both mice and humans. We purified the CR2-IgG construct from mouse B myeloma cell line supernatants, J558L-CR2-IgG, by protein G affinity chromatography. The CR2-IgG construct was used for capturing C3 fragments in microtiter wells and an anti-mouse or an anti-human-C3 antibody was used for detection of bound C3 fragments. Initially we tested the specificity of the assays with the use of purified C3 fragments. Further, with the use of the CR2-based assay, we measured an up to three-fold higher signal in activated mouse serum as compared to non-activated mouse serum, whereas activated serum from a C3 knock-out mouse gave no signal. We tested in vivo generated samples from a mouse experiment; complement activation was induced by injecting cobra venom factor or heat aggregated IgG into C57bl6 mice, followed by withdrawal of EDTA blood samples at different time points and measurement of iC3b/C3dg. We observed a clear time-dependent distinction in signals between samples with expected high and low complement activation. Furthermore, with the use of the assay for human C3 fragments, we observed that patients with systemic lupus erythematosus (SLE) (n = 144) had significantly higher iC3b/C3dg levels as compared to healthy individuals (n = 144) (p < 0.0001). We present two functional immunoassays, that are able to measure systemic levels of the C3-activation products iC3b and C3dg in mice and humans. To our knowledge, these are the first assays for complement activation that use a physiological relevant capture construct such as CR2. These assays will be a relevant tool when investigating mouse models and human diseases involving the complement system.

Dataset Information

Therapeutic control of complement activation at the level of the central component C3.

Publications

Therapeutic control of complement activation at the level of the central component C3.

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