Electrophysiological characteristics of primary afferent fibers after systemic administration of anti-GD2 ganglioside antibody

Abstract

An animal model showing mechanical allodynia following systemic bolus injection of a human/mouse chimeric monoclonal antibody to the GD2 ganglioside (ch14.18) has been established (e.g. pain behavior generated by a light tactile stimulus). This is of clinical relevance since ch14.18 is a promising experimental treatment for pediatric neuroblastoma. The present study examined the hypothesis that allodynic effects of the anti-GD2 antibody are mediated by actions on cutaneous nerve fibers. After determining the basal magnitude of the mechanical stimulus required to produce withdrawal, ch14.18, a murine form of the anti-GD2 antibody of IgG2a isotype (14G2a), a control murine anti-melanoma antibody of IgG2a isotype (9.2.27) or saline was injected through a previously implanted jugular cannula. The experimenter was blinded to the syringe contents. Withdrawal threshold was tested at 15 min intervals for 1 h. After administration of either ch14.18 or 14G2a mechanical allodynia typically started within the first 15 min and persisted throughout the hour of behavioral testing. In the control antibody group, a modest change in tactile withdrawal threshold was observed at the 60 min time point only. Rats were then anesthetized with pentobarbital and prepared for single fiber recordings from the sural nerve. Fibers were classified based on conduction velocity, as A beta (> 25 m/s), A delta (2-25 m/s) or C (< 2 m/s). Background activity (BA) was observed in a significant number of A delta (12/61) and C (32/42) fibers in both anti-GD2 treated groups compared to the anti-melanoma antibody (1/17 A delta and 2/10 C fibers) and saline (0/26 A delta and 0/19 C fibers) treated groups. Mean mechanical threshold for A delta fibers in all three antibody treated groups was significantly reduced compared to the saline control; this was not observed for C-fibers in any group. Intravenous bolus injection (15 mg/kg) and infusion of lidocaine (plasma level 0.3-2.2 micrograms/ml) both reduced anti-GD2 associated BA. These data demonstrate that mechanical-allodynia could be produced by action(s) of the anti-GD2 antibody (direct or indirect) on peripheral nerves and suggest intravenous lidocaine as part of the analgesic regimen accompanying anti-GD2 antibody treatment.