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

Abstract

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.

Pharmacokinetics and pharmacodynamics of ch14.18/CHO in relapsed/refractory high-risk neuroblastoma patients treated by long-term infusion in combination with IL-2

“…We observed the development of HACA in 19% of analyzed patients (10/53). These data are in line with our previous report of HACA development in 21% patients treated with STI of ch14.18/CHO 6 and indicate a similar immunogenicity of ch14.18/CHO irrespective of the treatment regimen. For further analysis of HACA effects on ch14.18/CHO PK parameters we divided HACA-positive patients into two cohorts according to the level of HACA in analyzed serum samples: HACA-high responders (mean HACA value 10 mg/ml) and HACA-low responders (mean HACA value < 10 mg/ml).…”

“…In order to ameliorate pain as the main on-target side effect of this treatment, we piloted a 10-day continuous LTI with ch14.18/CHO using the established cumulative dose of 100 mg/m2/cycle. 6 Here, we report population PK and PD with this novel method of ch14.18/CHO delivery. We first established an improved ELISA technique compared to our previous report, 9 following a three-step analysis procedure with an optimized limit of detection of 58 ng/ml ch14.18/CHO (Fig.…”

“…As we previously reported, the completion of a Phase 1 study with ch14.18/CHO delivered in the STI setting, 6 we used samples from these patients for reanalysis and comparison to LTI of ch14.18/CHO. This investigation revealed similar clearance parameters of LTI compared with STI of ch14.18/CHO.…”

“…For that reason, a Phase 1 bridging study was initiated to assess safety, PK and activity profiles of the recloned Ab ch14.18/CHO. 6 Analysis of 16 patients revealed that the toxicity profile, clinical activity and PK of ch14.18/CHO given as 8 h STI on five consecutive days (5 £ 20 mg/m2) were comparable to ch14.18 produced in SP2/0 cells, allowing for approval of the use in randomized clinical trials. 6 One major obstacle associated with anti-GD2 Ab therapies is the induction of neuropathic pain, 4,6 which is an on-target side effect not observed with other human/mouse chimeric mAbs.…”

“…6 Analysis of 16 patients revealed that the toxicity profile, clinical activity and PK of ch14.18/CHO given as 8 h STI on five consecutive days (5 £ 20 mg/m2) were comparable to ch14.18 produced in SP2/0 cells, allowing for approval of the use in randomized clinical trials. 6 One major obstacle associated with anti-GD2 Ab therapies is the induction of neuropathic pain, 4,6 which is an on-target side effect not observed with other human/mouse chimeric mAbs. In animal models, which approximate the pain associated with anti-GD2 Ab in humans in terms of timing and quality, GD2-specific binding to Ad-and C pain fibers results in decreased mechanical stimulus thresholds.…”