Chimeric antibody c.8B6 to O-acetyl-GD2 mediates the same efficient anti-neuroblastoma effects as therapeutic ch14.18 antibody to GD2 without antibody induced allodynia.

Abstract

BACKGROUND:

Anti-GD2 antibody is a proven therapy for GD2-positive 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 FINDINGS:

We 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/SIGNIFICANCE:

The 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.

• Authors: Mickaël Terme, Mylène Dorvillius, Denis Cochonneau, Tanguy Chaumette, Wenhua Xiao, Mitchell B Diccianni, Jacques Barbet, Alice L Yu, François Paris, Linda S Sorkin, Stéphane Birklé
• Journal: PloS one (PLoS One) Vol. 9 Issue 2 Pg. e87210 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24520328 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal
• Gangliosides
• ganglioside, GD2
• dinutuximab

Topics

• Acetylation
• Animals
• Antibodies, Monoclonal (administration & dosage, adverse effects, immunology)
• Antibody Specificity (immunology)
• Flow Cytometry
• Gangliosides (immunology)
• Humans
• Hyperalgesia (chemically induced, pathology)
• Injections, Intravenous
• Mice
• Neuroblastoma (immunology, pathology, therapy)
• Protein Binding
• Rats
• Rats, Sprague-Dawley