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

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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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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., Pribill, I., Glander, P., Bauer, S., Pistoia, V., Michon, J., Garaventa, A., & 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