Safety and pharmacokinetics of plasma-derived mannose-binding lectin (MBL) substitution in children with chemotherapy-induced neutropaenia

Frakking, Florine N. J.; Brouwer, Nannette; Wetering, Marianne D. van de; Budde, Ilona Kleine; Strengers, P. F. W.; Huitema, Alwin D. R.; Laursen, Inga; Houen, Gunnar; Caron, Huib N.; Dolman, Koert M.; Kuijpers, Taco W.

doi:10.1016/j.ejca.2008.11.036

Cited by 40 publications

(31 citation statements)

References 25 publications

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“…The infused MBL increases MBL/MASP-mediated complement activation and opsonophagocytosis of zymosan in vitro, albeit to a suboptimal extent. The calculated trough level of 1.0 g/ml MBL (26,38) is not sufficient to reach optimal serum opsonic function, which cannot be explained only by the 40% loss of C4-activating ability during purification of MBL from plasma (21). MBL substitution has shown to be clinically beneficial in patients treated on compassionate grounds as presented in case reports (40,41) and in preclinical studies with knockout mice (42), without chemotherapy treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The doses of MBL had been predicted to yield trough levels of 1.0 g/ml MBL, a level considered sufficient for opsonization in healthy control sera (26). Although the MBL trough level was reached, the levels of opsonophagocytosis were lower than expected.…”

Section: Discussionmentioning

confidence: 99%

“…The half-life of the infused MBL was 36.4 h (range, 23.7-66.6 h). None of the participating patients showed any adverse effects to the infused MBL, and no anti-MBL Abs were found 4 wk after the last MBL infusion (26).…”

mentioning

confidence: 99%

“…The set-up of the study and the pharmacokinetics and the safety of the infused MBL have been described by Frakking et al (26). In short, we aimed at an MBL trough level of 1.0 g/ml.…”

mentioning

confidence: 99%

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Mannose-Binding Lectin (MBL) Substitution: Recovery of Opsonic Function In Vivo Lags behind MBL Serum Levels

Brouwer

Frakking

Wetering

et al. 2009

The Journal of Immunology

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Mannose-binding lectin (MBL) deficiency is often associated with an increased risk of infection or worse prognosis in immunocompromised patients. MBL substitution in these patients might diminish these risks. We therefore performed an open, uncontrolled safety and pharmacokinetic MBL-substitution study in 12 pediatric oncology patients with chemotherapy-induced neutropenia. Twice weekly MBL infusions with plasma-derived MBL yielded MBL trough levels >1.0 μg/ml. We tested whether MBL substitution in vivo increased MBL-dependent complement activation and opsonophagocytosis of zymosan in vitro. Upon MBL substitution, opsonophagocytosis by control neutrophils increased significantly (p < 0.001) but remained suboptimal, although repeated MBL infusions resulted in improvement over time. The MBL-dependent MBL-associated serine protease (MASP)-mediated complement C3 and C4 activation also showed a suboptimal increase. To explain these results, complement activation was studied in detail. We found that in the presence of normal MASP-2 blood levels, MASP-2 activity (p < 0.0001) was reduced as well as the alternative pathway of complement activation (p < 0.05). This MBL-substitution study demonstrates that plasma-derived MBL infusions increase MBL/MASP-mediated C3 and C4 activation and opsonophagocytosis, but that higher circulating levels of plasma-derived MBL are required to achieve MBL-mediated complement activation comparable to healthy controls. Other patient cohorts should be considered to demonstrate clinical efficacy in phase II/III MBL-substitution studies, because we found a suboptimal recovery of (in vitro) biological activity upon MBL substitution in our neutropenic pediatric oncology cohort.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…The set-up of the study and the pharmacokinetics and the safety of the infused MBL have been described by Frakking et al (26). In short, we aimed at an MBL trough level of 1.0 g/ml.…”

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confidence: 99%

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Mannose-Binding Lectin (MBL) Substitution: Recovery of Opsonic Function In Vivo Lags behind MBL Serum Levels

Brouwer

Frakking

Wetering

et al. 2009

The Journal of Immunology

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“…The conflicting outcomes of these studies clearly underline that more research is required to unravel the exact relationship among MBL2 genotypes, MBL serum levels, and the occurrence of neutropenic events in cancer patients treated with chemotherapy. We, therefore, feel that the initiation of studies on MBL replacement therapy, as has occurred in patients with multiple myeloma or children with chemotherapy-induced neutropenia, is premature [50].…”

Section: Discussionmentioning

confidence: 99%

Effects of Mannose-Binding Lectin Polymorphisms on Irinotecan-Induced Febrile Neutropenia

Bol

Jong

Schaik³

et al. 2010

The Oncologist

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Objective. Mannose-binding lectin (MBL) is important in the innate immune response. MBL2 gene polymorphisms affect MBL expression, and genotypes yielding low MBL levels have been associated with an elevated risk for infections in hematological cancer patients undergoing chemotherapy. However, these reported associations are inconsistent, and data on patients with solid tumors are lacking. Here, we investigated the effects of MBL2 genotypes on irinotecan-induced febrile neutropenia in patients with solid tumors.Patients and Methods. Irinotecan-treated patients were genotyped for the MBL2 gene. Two promoter (؊550 H/L and ؊221 X/Y) and three exon polymorphisms (52 A/D, 54 A/B, and 57 A/C) were determined, together with known risk factors for irinotecan-induced toxicity. Neutropenia and febrile neutropenia were recorded during the first course.Results

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Risk of infection and sepsis in severely injured patients related to single nucleotide polymorphisms in the lectin pathway

Bronkhorst

Lomax

Vossen

et al. 2013

British Journal of Surgery

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Safety and pharmacokinetics of plasma-derived mannose-binding lectin (MBL) substitution in children with chemotherapy-induced neutropaenia

Cited by 40 publications

References 25 publications

Mannose-Binding Lectin (MBL) Substitution: Recovery of Opsonic Function In Vivo Lags behind MBL Serum Levels

Mannose-Binding Lectin (MBL) Substitution: Recovery of Opsonic Function In Vivo Lags behind MBL Serum Levels

Effects of Mannose-Binding Lectin Polymorphisms on Irinotecan-Induced Febrile Neutropenia

Risk of infection and sepsis in severely injured patients related to single nucleotide polymorphisms in the lectin pathway

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