Disposition of Recombinant Human Interleukin‐10 in Subjects with Various Degrees of Renal Function

Andersen, Scott R.; Lambrecht, Lawrence J.; Swan, Suzanne K.; Cutler, David L.; Radwanski, Elaine; Affrime, Melton B.; Garaud, Jean–Jacques

doi:10.1177/00912709922011773

Cited by 23 publications

(9 citation statements)

References 15 publications

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“…8), which is in agreement with previous studies (Andersen et al, 1999;Rachmawati et al, 2004a). Coupling of M6P groups to IL10 induced a shift in biodistribution of IL10 from the kidneys to the fibrotic liver.…”

Section: Resultssupporting

confidence: 92%

Chemical Modification of Interleukin-10 with Mannose 6-Phosphate Groups Yields a Liver-Selective Cytokine

Rachmawati¹,

Reker‐Smit²,

Hooge³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Cytokines are considered a promising immunotherapy for chronic diseases, because of their potency and fundamental roles in pathological processes. However, their therapeutic use is limited because of their poor pharmacokinetics and pleiotropic effects in various organs. These problems may be overcome by cell-specific delivery of the cytokine. This approach involves chemical modification of the protein with homing devices that recognize receptors on target cells. The cytokine interleukin-10 (IL10) may be valuable as a therapeutic cytokine for patients with liver cirrhosis. However, its rapid renal elimination and general immunosuppressive activities limit therapeutic use. We therefore aim to target this cytokine in the liver, in particular to fibrogenic hepatic stellate cells (HSCs). We show that IL10 is successfully modified with mannose 6-phosphate (M6P), which is a homing device for the mannose 6-phosphate/insulin-like growth factor II (M6P/IGFII) receptor expressed on activated HSCs. Chemical modification did not diminish IL10 efficacy with regard to in vitro anti-inflammatory (lipopolysaccharide-stimulated tumor necrosis factor ␣ release) and antifibrotic (collagen deposition and degradation) activities. Biodistribution studies with radiolabeled M6P-IL10 and IL10 in rats with liver fibrosis showed that modification with M6P groups induced a shift in the distribution from the kidneys (IL10) to the liver (M6P-IL10). Hepatocellular binding of M6P-IL10 occurred via M6P/IGFII receptors and scavenger receptors, indicating that not only HSCs but also Kupffer and endothelial cells are target cells. IL10 did not bind to these receptors. We conclude that we prepared an active and liver-specific form of the cytokine IL10 that can be evaluated for its efficacy to treat liver diseases.

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Section: Resultssupporting

confidence: 92%

Chemical Modification of Interleukin-10 with Mannose 6-Phosphate Groups Yields a Liver-Selective Cytokine

Rachmawati¹,

Reker‐Smit²,

Hooge³

et al. 2007

Drug Metab Dispos

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“…Because hIL-10 is nonglycosylated, it is cleared mainly through the kidney, as indicated by the increased t 1/2 and AUC of IL-10 in patients with moderate to severe renal insufficiencies. Administration of IL-10 did not produce adverse effects in this patient population (Andersen et al, 1999). Subcutaneous administration of IL-10 resulted in slow absorption from the IL-10 depot formed at the injection site, which reached C max at 2 to 6.5 h post injection.…”

Section: A Phase I Trials In Healthy Volunteersmentioning

confidence: 66%

Interleukin-10 Therapy—Review of a New Approach

2003

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“…2). This is not surprising because the half‐lives of cytokines are much shorter (on the order of minutes in the case of interleukin‐10)26 than the half‐lives of immunoglobulins (7 to 23 days) 27. The observed decrease of cytokines before the 5th apheresis is because of high‐dose steroid treatment in the first three weeks of the study.…”

Section: Discussionmentioning

confidence: 99%

Plasma filtration in the treatment of graves' ophthalmopathy: A randomized study

Ceeová

Skacha

et al. 2010

J of Clinical Apheresis

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The aim of this study was to perform a randomized study to evaluate the role of plasma filtration in the treatment of severe thyroid-associated ophthalmopathy (TAO). 20 patients were enrolled, and all patients were treated with methylprednisolone IV pulses. 10 randomly chosen patients were also subjected to plasma filtration (twice weekly in Weeks 1, 2, 4, 7, and 10). The procedure proved to be safe. All immunoglobulin classes as well as autoantibodies directed against thyroglobulin, thyroid peroxidase, and TSH receptor exhibited statistically significantly decreases. Some markers of cell-mediated immunity such as soluble antigen CD30 and monocyte chemotactic protein 1 decreased, but serum levels of other markers such as CD40 ligand and soluble protein Fas/Apo-1 did not change significantly. The decrease of immunoglobulins was long lasting, whereas cytokine levels returned to basal values before the next apheresis. Although the clinical activity score (CAS) dropped in all patients, it occurred more rapidly in patients treated with plasma filtration. The CAS difference between the two groups was statistically significant (p = 0.027). The amplitude of visual evoked potentials improved after 3 months in the plasma filtration group. At the end of the study, there was no difference between patients treated with aphereses and the control group. Eye muscle width and proptosis measured by CT scan did not differ between the two groups. We conclude that apheresis can decrease disease activity more rapidly than standard high-dose IV glucocorticoid therapy. Whether this superior treatment effect could potentially avoid surgical procedures remains to be determined.

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Disposition of Recombinant Human Interleukin‐10 in Subjects with Various Degrees of Renal Function

Cited by 23 publications

References 15 publications

Chemical Modification of Interleukin-10 with Mannose 6-Phosphate Groups Yields a Liver-Selective Cytokine

Chemical Modification of Interleukin-10 with Mannose 6-Phosphate Groups Yields a Liver-Selective Cytokine

Interleukin-10 Therapy—Review of a New Approach

Plasma filtration in the treatment of graves' ophthalmopathy: A randomized study

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