The effect of anti-L-selectin (aselizumab) in multiple traumatized patients—Results of a phase II clinical trial*

Seekamp, Andreas; Griensven, Martijn van; Dhondt, Erwin; Diefenbeck, Michael; Demeyer, Ignace; Vundelinckx, G.; Haas, Norbert; Schaechinger, Ulrich; Wolowicka, L; Rammelt, Stefan; Stroobants, Jan; Marzi, Ingo; Brambrink, Ansgar M.; Dziurdzik, Piotr; Gąsiorowski, Jacek; Redl, Heinz; Beckert, Michael; Khan-Boluki, J.

doi:10.1097/01.ccm.0000142396.59236.f3

Cited by 35 publications

(32 citation statements)

References 29 publications

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“…Adhesion blocking strategies have been attempted in humans with limited success. In a phase II double-blind, randomized, placebo-controlled trial involving 84 trauma patients, intravenous aselizumab (humanized monoclonal anti-L-selectin antibody) did not alter adverse outcomes related to multi-organ failure and ALI [42 ]. There was a trend towards increased infection rates and leucopenia, however.…”

Section: Integrinsmentioning

confidence: 96%

Neutrophil granule contents in the pathogenesis of lung injury

Moraes

Zurawska

Downey

2006

Current Opinion in Hematology

196

132

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The primary function of neutrophils in the innate immune response--to contain and kill invading microbial pathogens--is achieved through a series of rapid and coordinated responses culminating in phagocytosis and intracellular killing of the pathogens. Neutrophils have a potent antimicrobial arsenal that includes oxidants, proteinases, and cationic peptides. Reactive oxygen species such as oxygen are produced by the phagocyte NADPH oxidase and are microbicidal. Granules within the neutrophil cytoplasm contain potent proteolytic enzymes and cationic proteins that can digest a variety of microbial substrates. These compounds are released directly into the phagosome, compartmentalizing both the pathogen and the cytotoxic products. Under pathological circumstances, however, unregulated release of microbicidal compounds into the extracellular space can paradoxically damage host tissues. Nonspecific inhibition of neutrophils is not clinically realistic, as it would leave the host vulnerable to infection. As the mechanisms of action of neutrophil granule contents are elucidated, therapeutic targets will be identified that will allow for suppression of neutrophils' detrimental effects while avoiding inhibition of their beneficial effects.

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Section: Integrinsmentioning

confidence: 96%

Neutrophil granule contents in the pathogenesis of lung injury

Moraes

Zurawska

Downey

2006

Current Opinion in Hematology

196

132

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“…Of note, available clinical data suggest that anti selectin drug delivery directly to the target organ (e.g., cylexin in the cardiopulmonary bypass circuit [128] or inhaled/ subcutaneous bimosiamose [129][130][131][132]) is more effective than the systemic treatment [123][124][125][126]. However, these results may be ascribed to the fact that, apart from GMI-1070, pan-selectin therapies were never tested systemically, like antiselectin antibodies or PSGL-1-Ig fusion protein [123][124][125][126]. Pan-selectin antagonists may overcome the functional redundancy among selectins in leukocyte trafficking, being a more powerful tool for the inhibition of selectin-mediated adhesion during inflammatory pathologies (also discussed in [132]).…”

Section: Antiselectin Therapeutic Aproachesmentioning

confidence: 99%

“…For instance, intravenous treatment with a humanized anti-E-sel antibody (CDP850) was not effective in ameliorating the clinical outcome in patients with psoriasis, whereas therapy with aselizumab, a humanized mono clonal anti-L-sel antibody, did not protect patients from multiple organ failures after trauma and was associated with an increased risk of infections [123,124]. Inhibition of selectin function by a recombinant human PSGL-1-IgG fusion protein (YSPSL) did not reduce the reperfusion-induced damage in patients with kidney transplantation and myocardial infraction [125,126], while YSPSL improved early liver allograft function after liver transplantation [127].…”

Section: Antiselectin Therapeutic Aproachesmentioning

confidence: 99%

Selectins and Their Ligands as Potential Immunotherapeutic Targets in Neurological Diseases

Angiari

Constantin

2013

Immunotherapy

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Selectins are a family of adhesion receptors that bind to highly glycosylated molecules expressed on the surface of leukocytes and endothelial cells. The interactions between selectins and their ligands control tethering and rolling of leukocytes on the vascular wall during the process of leukocyte migration into the tissues under physiological and pathological conditions. In recent years, it has been shown that leukocyte recruitment in the CNS plays a pivotal role in diseases such as multiple sclerosis, ischemic stroke, epilepsy and traumatic brain injury. In this review, we discuss the role of selectins in leukocyte-endothelial interactions in the pathogenesis of neurological diseases, highlighting new findings suggesting that selectins and their ligands may represent novel potential therapeutic targets for the treatment of CNS diseases.

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“…Blocking the activity of selectins in several clinical disorders failed to be effective as antiinflammatory drug [10,100]. In a randomized placebocontrolled trial, the clinical efficacy and side effects of the humanized anti E-selectin antibody CDP850 in moderate to severe chronic plaque psoriasis were investigated [101].…”

Section: Clinical Trials Of Autoimmune Diseases Using Anti-adhesive Smentioning

confidence: 99%

“…However, the treatment had no therapeutic effect, because psoriasis area and severity were unaffected. In a phase II trial with multiple traumatized patients, the anti-Lselectin antibody aselizumab was administered within 6 hours of the traumatic event [100]. The therapy presented no significant efficacy compared with placebo.…”

Section: Clinical Trials Of Autoimmune Diseases Using Anti-adhesive Smentioning

confidence: 99%

Therapeutic Strategies in Autoimmune Diseases by Interfering with Leukocyte Endothelium Interaction

Rychly¹,

Nebe²

2006

CPD

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The interaction of leukocytes with the vessel endothelium to facilitate the extravasation into the tissue represents a key process of the body's defense mechanisms. Excessive recruitment of leukocytes into the inflamed tissue in chronic diseases like autoimmune disorders could be prevented by interfering with the mechanisms of leukocyte extravasation. Significant progress in elucidating the molecular basis of the trafficking of leukocytes from the blood stream to the extravascular tissue has been achieved that enables new strategies for therapeutic approaches. The multistep process of leukocyte rolling, firm adhesion and transmigration through the endothelial wall is facilitated by a dynamic interplay of adhesion receptors on both leukocytes and endothelial cells as well as chemokines. In preclinical studies using various animal models, promising results have been received demonstrating that blocking of adhesion receptors of the selectin and integrin families improved the inflammation process in models of ulcerative colitis, autoimmune encephalomyelitis or contact hypersensitivity. In addition to the targeting of adhesion receptors by antibodies, small molecules that mimic epitopes of adhesion receptor ligands have been developed and successfully applied in animal models. Clinical studies revealed a limited response using antibodies to selectins or LFA-1 integrins compared with animal models. However, using humanized antibodies to the alpha4- integrin subunit significant efficacy has been demonstrated in autoimmune diseases like psoriasis, multiple sclerosis and inflammatory bowel disease.

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The effect of anti-L-selectin (aselizumab) in multiple traumatized patients—Results of a phase II clinical trial*

Cited by 35 publications

References 29 publications

Neutrophil granule contents in the pathogenesis of lung injury

Neutrophil granule contents in the pathogenesis of lung injury

Selectins and Their Ligands as Potential Immunotherapeutic Targets in Neurological Diseases

Therapeutic Strategies in Autoimmune Diseases by Interfering with Leukocyte Endothelium Interaction

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