APT070 inhibits complement activation during in vitro cardiopulmonary bypass

Silva, Ravi J. De; Vuylsteke, Alain; Fritchley, Sarah J.; Trull, Andrew K.; Dunning, John; Wallwork, J.

doi:10.1016/j.ejcts.2006.03.012

Cited by 7 publications

(4 citation statements)

References 24 publications

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“…Therefore, clinical trials have been stopped (145). Similar substances such as sCR1-sLe x / TP20 with an improved structure (148) and Microcept/APT070 (149) are currently under investigation for the treatment of diseases such as acute myocardial infarction, stroke and inflammatory diseases but have not entered clinical evaluation (150).…”

Section: Immunomodulation Of Complementmentioning

confidence: 99%

New Insights of an Old Defense System: Structure, Function, and Clinical Relevance of the Complement System

Ehrnthaller

Ignatius

Gebhard

et al. 2010

Mol Med

190

154

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The complement system was discovered a century ago as a potent defense cascade of innate immunity. After its first description, continuous experimental and clinical research was performed, and three canonical pathways of activation were established. Upon activation by traumatic or surgical tissue damage, complement reveals beneficial functions of pathogen and danger defense by sensing and clearing injured cells. However, the latest research efforts have provided a more distinct insight into the complement system and its clinical subsequences. Complement has been shown to play a significant role in the pathogenesis of various inflammatory processes such as sepsis, multiorgan dysfunction, ischemia/reperfusion, cardiovascular diseases and many others. The three well-known activation pathways of the complement system have been challenged by newer findings that demonstrate direct production of central complement effectors (for example, C5a) by serine proteases of the coagulation cascade. In particular, thrombin is capable of producing C5a, which not only plays a decisive role on pathogens and infected/damaged tissues, but also acts systemically. In the case of uncontrolled complement activation, "friendly fire" is generated, resulting in the destruction of healthy host tissue. Therefore, the traditional research that focuses on a mainly positive-acting cascade has now shifted to the negative effects and how tissue damage originated by the activation of the complement can be contained. In a translational approach including structure-function relations of this ancient defense system, this review provides new insights of complement-mediated clinical relevant diseases and the development of complement modulation strategies and current research aspects.

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Section: Immunomodulation Of Complementmentioning

confidence: 99%

New Insights of an Old Defense System: Structure, Function, and Clinical Relevance of the Complement System

Ehrnthaller

Ignatius

Gebhard

et al. 2010

Mol Med

190

154

View full text Add to dashboard Cite

show abstract

“…This was in contrast to a comparator, C1-inhibitor, where a protective effect was shown. In vitro, APT070 was shown to inhibit complement activation in a cardiopulmonary bypass circuit model, and a reduction in the neutrophil activation marker CD11b was also observed 164 .…”

Section: Apt070 (Mirococept)mentioning

confidence: 94%

Soluble Complement Receptor 1 Therapeutics

Hardy¹,

Rowe²,

Wymann³

2022

J Immunological Sci

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Human Complement Receptor 1 (CR1/CD35) is a potent negative regulator of the complement system. Its mechanism of action is through interaction with the complement activation fragments, C3b and C4b to mediate decay acceleration of the C3 and C5 convertase complexes as well as cleavage of both ligands into inactive fragments via cofactor activity. The result is inhibition of the classical, lectin, and alternative complement pathways. This article will focus on recombinant soluble forms of CR1 that have been generated as potential therapeutics for complement-mediated disorders. Specifically, we will review and contrast the in vitro and in vivo properties of: sCR1 (BRL55730/TP10/CDX-1135), the soluble full-length extracellular domain of human CR1; sCR1-sLex (TP20), a glyco-engineered version of sCR1 additionally targeted to activated endothelium; APT070 (Mirococept), a CR1 fragment conjugated to a myristoylated peptide to enhance tissue targeting; and CSL040, a soluble truncated version of the CR1 extracellular domain which exhibits altered potency and pharmacokinetic properties as compared to the parental molecule. The data obtained from studies on the effects of these CR1-based molecules in animal models of disease and their therapeutic applications will also be discussed.

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“…Experimental and clinical studies evaluating different complement inhibitors including APT070 and TP10 (C3 and C5 activation inhibitor) and Pexelizumab (a recombinant antibody binding to C5) have reported a significant reduction in active complement proteins, and better protection of the lungs and myocardium during CPB, and improvement in patient outcomes (211)(212)(213). However, some of these studies failed to show an association between diminished complement activation and inflammation.…”

Section: Complement Inhibitionmentioning

confidence: 99%

Inflammation and Oxidative Stress in the Context of Extracorporeal Cardiac and Pulmonary Support

2022

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Extracorporeal circulation (ECC) systems, including cardiopulmonary bypass, and extracorporeal membrane oxygenation have been an irreplaceable part of the cardiothoracic surgeries, and treatment of critically ill patients with respiratory and/or cardiac failure for more than half a century. During the recent decades, the concept of extracorporeal circulation has been extended to isolated machine perfusion of the donor organ including thoracic organs (ex-situ organ perfusion, ESOP) as a method for dynamic, semi-physiologic preservation, and potential improvement of the donor organs. The extracorporeal life support systems (ECLS) have been lifesaving and facilitating complex cardiothoracic surgeries, and the ESOP technology has the potential to increase the number of the transplantable donor organs, and to improve the outcomes of transplantation. However, these artificial circulation systems in general have been associated with activation of the inflammatory and oxidative stress responses in patients and/or in the exposed tissues and organs. The activation of these responses can negatively affect patient outcomes in ECLS, and may as well jeopardize the reliability of the organ viability assessment, and the outcomes of thoracic organ preservation and transplantation in ESOP. Both ECLS and ESOP consist of artificial circuit materials and components, which play a key role in the induction of these responses. However, while ECLS can lead to systemic inflammatory and oxidative stress responses negatively affecting various organs/systems of the body, in ESOP, the absence of the organs that play an important role in oxidant scavenging/antioxidative replenishment of the body, such as liver, may make the perfused organ more susceptible to inflammation and oxidative stress during extracorporeal circulation. In the present manuscript, we will review the activation of the inflammatory and oxidative stress responses during ECLP and ESOP, mechanisms involved, clinical implications, and the interventions for attenuating these responses in ECC.

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APT070 inhibits complement activation during in vitro cardiopulmonary bypass

Abstract: APT070 significantly inhibits complement and neutrophil activation. This result may have considerable implications, especially if it can be shown to decrease the inflammatory sequelae of CPB.

Cited by 7 publications

References 24 publications

New Insights of an Old Defense System: Structure, Function, and Clinical Relevance of the Complement System

New Insights of an Old Defense System: Structure, Function, and Clinical Relevance of the Complement System

Soluble Complement Receptor 1 Therapeutics

Inflammation and Oxidative Stress in the Context of Extracorporeal Cardiac and Pulmonary Support

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