Ch14.18 antibody produced in CHO cells in relapsed or refractory Stage 4 neuroblastoma patients: a SIOPEN Phase 1 study.
OBJECTIVE
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).


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.


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/m(2)/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 ± 1.9h for ch14.18/CHO and 25.0 h ± 1.9 h for ch14.18/SP2/0. The biodistribution of (125)I-ch14.18/CHO in mice with neuroblastoma was identical to (125)I-ch14.18/SP2/0, indicating GD 2 targeting activity in vivo. 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.
Children's Cancer Research Institute and St. Anna Children's Hospital and Department of Paediatric and Adolescent Medicine; Medical University; Vienna, Austria.
Ruth
R
Ladenstein
Silke
S
Weixler
Bianca
B
Baykan
Matthias
M
Bleeke
Renate
R
Kunert
Dietmar
D
Katinger
Ingrid
I
Pribill
Petra
P
Glander
Steffen
S
Bauer
Vito
V
Pistoia
Jean
J
Michon
Alberto
A
Garaventa
Holger N
HN
Lode
D000293:Adolescent; D000740:Anemia / Q000139:chemically induced; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D016466:CHO Cells; D002648:Child; D002675:Child, Preschool; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; C112746:dinutuximab
anti GD2; ch14.18/CHO; immunotherapy; monoclonal antibody; neuroblastoma