Ch14.18 antibody produced in CHO cells in relapsed or refractory stage 4 neuroblastoma patients

A SIOPEN phase 1 study

Ruth Ladenstein, Silke Weixler, Bianca Baykan, Matthias Bleeke, Renate Kunert, Dietmar Katinger, Ingrid Pribill, Petra Glander, Steffen Bauer, Vito Pistoia, Jean Michon, Alberto Garaventa, Holger N. Lode

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Purpose: This study aimed to assess the safety, pharmacokinetic and activity profiles of the human-mouse chimeric monoclonal anti-disialoganglioside GD2 antibody ch14.18 produced in Chinese hamster ovary (CHO) cells (ch14.18/CHO). Results: A total of 41 ch14.18/CHO courses were given (10 × 3 courses, 5 × 2 courses, 1 × 1 course). Side effects were similar in expectedness, frequency and magnitude to those reported for ch14.18/SP2/0. The dose level of 20 mg/m2/day was confirmed. Toxicity was reversible and no treatment-related deaths occurred. In children, the peak plasma concentration was 16.51 μg/ml ± 5.9 μg/ml and the half-life was 76.91 h ± 52.5 h. A partial response following ch14.18/CHO was observed in 2/7 patients with residual disease. In mice, the half-lives were 22.7 h ± 1.9 h for ch14.18/CHO and 25.0 h ± 1.9 h for ch14.18/SP2/0. The biodistribution of 125I-ch14.18/CHO in mice with neuroblastoma was identical to 125I-ch14.18/SP2/0, indicating GD2 targeting activity in vivo. Methods: Sixteen children with recurrent/refractory neuroblastoma (median age 7.6 y) were enrolled in this Phase 1 dose-finding study. Patients received ch14.18/CHO courses of 10, 20 or 30 mg/m 2/day as an eight-hour infusion over five consecutive days. Three courses at the same dose level were allowed unless disease progressed. Clearance and biodistribution of radiolabelled ch14.18/CHO in Balb/c and A/J mice were analyzed. Ch14.18 produced in CHO cells showed an unchanged toxicity profile and pharmacokinetics in neuroblastoma patients compared with ch14.18 produced in SP2/0 cells, and evidence of clinical activity was observed. In mice, analysis of pharmacokinetics and biodistribution showed comparable results between ch14.18/CHO and ch14.18/SP2/0. Based on these results, ch14.18/CHO was accepted for prospective clinical evaluation.

Original languageEnglish
Pages (from-to)801-809
Number of pages9
JournalmAbs
Volume5
Issue number5
DOIs
Publication statusPublished - Sep 2013

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Cricetulus
Neuroblastoma
Ovary
Antibodies
ch14.18 monoclonal antibody
Pharmacokinetics
Human Activities
Half-Life

Keywords

  • Anti GD2
  • Ch14.18/CHO
  • Immunotherapy
  • Monoclonal antibody
  • Neuroblastoma

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Ladenstein, R., Weixler, S., Baykan, B., Bleeke, M., Kunert, R., Katinger, D., ... Lode, H. N. (2013). Ch14.18 antibody produced in CHO cells in relapsed or refractory stage 4 neuroblastoma patients: A SIOPEN phase 1 study. mAbs, 5(5), 801-809. https://doi.org/10.4161/mabs.25215

Ch14.18 antibody produced in CHO cells in relapsed or refractory stage 4 neuroblastoma patients : A SIOPEN phase 1 study. / Ladenstein, Ruth; Weixler, Silke; Baykan, Bianca; Bleeke, Matthias; Kunert, Renate; Katinger, Dietmar; Pribill, Ingrid; Glander, Petra; Bauer, Steffen; Pistoia, Vito; Michon, Jean; Garaventa, Alberto; Lode, Holger N.

In: mAbs, Vol. 5, No. 5, 09.2013, p. 801-809.

Research output: Contribution to journalArticle

Ladenstein, R, Weixler, S, Baykan, B, Bleeke, M, Kunert, R, Katinger, D, Pribill, I, Glander, P, Bauer, S, Pistoia, V, Michon, J, Garaventa, A & Lode, HN 2013, 'Ch14.18 antibody produced in CHO cells in relapsed or refractory stage 4 neuroblastoma patients: A SIOPEN phase 1 study', mAbs, vol. 5, no. 5, pp. 801-809. https://doi.org/10.4161/mabs.25215
Ladenstein, Ruth ; Weixler, Silke ; Baykan, Bianca ; Bleeke, Matthias ; Kunert, Renate ; Katinger, Dietmar ; Pribill, Ingrid ; Glander, Petra ; Bauer, Steffen ; Pistoia, Vito ; Michon, Jean ; Garaventa, Alberto ; Lode, Holger N. / Ch14.18 antibody produced in CHO cells in relapsed or refractory stage 4 neuroblastoma patients : A SIOPEN phase 1 study. In: mAbs. 2013 ; Vol. 5, No. 5. pp. 801-809.
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T1 - Ch14.18 antibody produced in CHO cells in relapsed or refractory stage 4 neuroblastoma patients

T2 - A SIOPEN phase 1 study

AU - Ladenstein, Ruth

AU - Weixler, Silke

AU - Baykan, Bianca

AU - Bleeke, Matthias

AU - Kunert, Renate

AU - Katinger, Dietmar

AU - Pribill, Ingrid

AU - Glander, Petra

AU - Bauer, Steffen

AU - Pistoia, Vito

AU - Michon, Jean

AU - Garaventa, Alberto

AU - Lode, Holger N.

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N2 - Purpose: This study aimed to assess the safety, pharmacokinetic and activity profiles of the human-mouse chimeric monoclonal anti-disialoganglioside GD2 antibody ch14.18 produced in Chinese hamster ovary (CHO) cells (ch14.18/CHO). Results: A total of 41 ch14.18/CHO courses were given (10 × 3 courses, 5 × 2 courses, 1 × 1 course). Side effects were similar in expectedness, frequency and magnitude to those reported for ch14.18/SP2/0. The dose level of 20 mg/m2/day was confirmed. Toxicity was reversible and no treatment-related deaths occurred. In children, the peak plasma concentration was 16.51 μg/ml ± 5.9 μg/ml and the half-life was 76.91 h ± 52.5 h. A partial response following ch14.18/CHO was observed in 2/7 patients with residual disease. In mice, the half-lives were 22.7 h ± 1.9 h for ch14.18/CHO and 25.0 h ± 1.9 h for ch14.18/SP2/0. The biodistribution of 125I-ch14.18/CHO in mice with neuroblastoma was identical to 125I-ch14.18/SP2/0, indicating GD2 targeting activity in vivo. Methods: Sixteen children with recurrent/refractory neuroblastoma (median age 7.6 y) were enrolled in this Phase 1 dose-finding study. Patients received ch14.18/CHO courses of 10, 20 or 30 mg/m 2/day as an eight-hour infusion over five consecutive days. Three courses at the same dose level were allowed unless disease progressed. Clearance and biodistribution of radiolabelled ch14.18/CHO in Balb/c and A/J mice were analyzed. Ch14.18 produced in CHO cells showed an unchanged toxicity profile and pharmacokinetics in neuroblastoma patients compared with ch14.18 produced in SP2/0 cells, and evidence of clinical activity was observed. In mice, analysis of pharmacokinetics and biodistribution showed comparable results between ch14.18/CHO and ch14.18/SP2/0. Based on these results, ch14.18/CHO was accepted for prospective clinical evaluation.

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