title: Pharmacokinetics and pharmacodynamics of ch14.18/CHO in relapsed/refractory high-risk neuroblastoma patients treated by long-term infusion in combination with IL-2.
abstract: Ch14.18 manufactured in Chinese hamster ovary (CHO) cells is currently being evaluated in clinical trials. Short-term infusion (STI) (8-20 h/day; 4-5 days) of 100 mg/m2 ch14.18/CHO (dinutiximab β) per cycle in combination with cytokines is standard treatment of neuroblastoma (NB) patients. As pain is a limiting factor, we investigated a novel delivery method by continuous long-term infusion (LTI) of 100 mg/m2 over 10 days. 53 NB patients were treated with 5-6 cycles of 6 × 106 IU/m2 subcutaneous interleukin-2 (d 1-5, 8-12), LTI of 100 mg/m2 ch14.18/CHO (d 8-18) and 160 mg/m2 oral 13-cis-retinoic acid (d 22-35). Human anti-chimeric antibody (HACA), antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity were determined. With LTI, we observed a maximum concentration of ch14.18/CHO (Cmax) of 12.56 ± 0.68 µg/ml and a terminal half-life time (t1/2 β) of 32.7 ± 16.2 d. The clearance values for LTI and STI of 0.54 ± 0.13 and 0.41 ± 0.29 L/d m2 and area under the serum concentration-time curve (AUC) values of 189.6 ± 41.4 and 284.8 ± 156.8 µg×d/ml, respectively, were not significantly different. Importantly, we detected ch14.18/CHO trough concentration of ≥ 1 µg/ml at time points preceding subsequent antibody infusions after cycle 1, allowing a persistent activation of antibody effector mechanisms over the entire treatment period of 6 months. HACA responses were observed in 10/53 (19%) patients, similar to STI (21%), indicating LTI had no effect on the immunogenicity of ch14.18/CHO. In conclusion, LTI of ch14.18/CHO induced effector mechanisms over the entire treatment period, and may therefore emerge as the preferred delivery method of anti-GD2 immunotherapy to NB patients.
authors.affiliation: a Department of Pediatric Oncology and Hematology , University Medicine Greifswald , Greifswald , Germany.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Siebert
authors.affiliation: a Department of Pediatric Oncology and Hematology , University Medicine Greifswald , Greifswald , Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Eger
authors.affiliation: a Department of Pediatric Oncology and Hematology , University Medicine Greifswald , Greifswald , Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Seidel
authors.affiliation: a Department of Pediatric Oncology and Hematology , University Medicine Greifswald , Greifswald , Germany.
authors.forename: Madlen
authors.initials: M
authors.lastname: Jüttner
authors.affiliation: a Department of Pediatric Oncology and Hematology , University Medicine Greifswald , Greifswald , Germany.
authors.forename: Maxi
authors.initials: M
authors.lastname: Zumpe
authors.affiliation: b Department of Clinical Pharmacology of the Center of Drug Absorption and Transport , University Medicine Greifswald , Greifswald , Germany.
authors.forename: Danilo
authors.initials: D
authors.lastname: Wegner
authors.affiliation: a Department of Pediatric Oncology and Hematology , University Medicine Greifswald , Greifswald , Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Kietz
authors.affiliation: a Department of Pediatric Oncology and Hematology , University Medicine Greifswald , Greifswald , Germany.
authors.forename: Karoline
authors.initials: K
authors.lastname: Ehlert
authors.affiliation: c Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne , UK.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Veal
authors.affiliation: b Department of Clinical Pharmacology of the Center of Drug Absorption and Transport , University Medicine Greifswald , Greifswald , Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Siegmund
authors.affiliation: d Department of Pharmacology , Martin Luther University , Halle , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Weiss
authors.affiliation: e Apeiron Biologics , Vienna , Austria.
authors.forename: Hans
authors.initials: H
authors.lastname: Loibner
authors.affiliation: f Children's Cancer Research Institute , Vienna , Austria.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ladenstein
authors.affiliation: a Department of Pediatric Oncology and Hematology , University Medicine Greifswald , Greifswald , Germany.
authors.forename: Holger N
authors.initials: HN
authors.lastname: Lode
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016466:CHO Cells; D002648:Child; D002675:Child, Preschool; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D007223:Infant; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D015474:Isotretinoin / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C508594:IL2 protein, human; D007376:Interleukin-2; C112746:dinutuximab; D015474:Isotretinoin
keywords: Ch14.18/CHO; HACA; immunotherapy; neuroblastoma; pharmacokinetics