Abstract
BackgroundAnti-GD2 antibody is a proven therapy for GD2-postive neuroblastoma. Monoclonal antibodies against GD2, such as chimeric mAb ch14.18, have become benchmarks for neuroblastoma therapies. Pain, however, can limit immunotherapy with anti-GD2 therapeutic antibodies like ch14.18. This adverse effect is attributed to acute inflammation via complement activation on GD2-expressing nerves. Thus, new strategies are needed for the development of treatment intensification strategies to improve the outcome of these patients.Methodology/Principal FindingsWe established the mouse-human chimeric antibody c.8B6 specific to OAcGD2 in order to reduce potential immunogenicity in patients and to fill the need for a selective agent that can kill neuroblastoma cells without inducing adverse neurological side effects caused by anti-GD2 antibody immunotherapy. We further analyzed some of its functional properties compared with anti-GD2 ch14.18 therapeutic antibody. With the exception of allodynic activity, we found that antibody c.8B6 shares the same anti-neuroblastoma attributes as therapeutic ch14.18 anti-GD2 mAb when tested in cell-based assay and in vivo in an animal model.Conclusion/SignificanceThe absence of OAcGD2 expression on nerve fibers and the lack of allodynic properties of c.8B6–which are believed to play a major role in mediating anti-GD2 mAb dose-limiting side effects–provide an important rationale for the clinical application of c.8B6 in patients with high-risk neuroblastoma.
Highlights
Neuroblastoma, a cancer derived from precursor cells of the sympathetic nervous system, is the most challenging malignancy of childhood, associated with the highest mortality rate in pediatric oncology; this underlies the need for novel therapeutic approaches [1,2]
Some patients have developed sensorimotor polyneuropathy with or without the syndrome of inappropriate antidiuretic hormone subsequent to treatment with anti-GD2 monoclonal antibodies [7]. These adverse effects were attributed to the mAb recognition of GD2 on the pituitary gland and on peripheral nerves followed by complement activation [8]
Anti-GD2 antibody is a proven therapy for GD2-postive neuroblastoma and mAb against GD2 and their derivatives, such as chimeric mAb ch14.18, have provided benchmarks for improving anti-GD2 therapy [3]
Summary
Neuroblastoma, a cancer derived from precursor cells of the sympathetic nervous system, is the most challenging malignancy of childhood, associated with the highest mortality rate in pediatric oncology; this underlies the need for novel therapeutic approaches [1,2]. A major advance in the treatment of these patients was immunotherapy with a chimeric anti-GD2 therapeutic antibody combined with IL-2 and GM-CSF which significantly improved event-free survival and overall survival in a phase III randomized clinical trial in children with high-risk neuroblastoma [3]. Some patients have developed sensorimotor polyneuropathy with or without the syndrome of inappropriate antidiuretic hormone subsequent to treatment with anti-GD2 monoclonal antibodies [7] These adverse effects were attributed to the mAb recognition of GD2 on the pituitary gland and on peripheral nerves followed by complement activation [8]. Can limit immunotherapy with anti-GD2 therapeutic antibodies like ch14.18 This adverse effect is attributed to acute inflammation via complement activation on GD2-expressing nerves. New strategies are needed for the development of treatment intensification strategies to improve the outcome of these patients
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