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

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.

Anti-GD2 MABS and Next-Generation mAb-Based Agents for Cancer Therapy

“…The less immunogenic chimeric c.8B6 with a human IgG1 isotype, retains the binding affinity and has been shown to have similar functional properties to ch14.18 both in vitro and in vivo, sharing the same anti-NBL effects but with much less allodynic activity [84]. The lack of OAc-GD2 expression on nerves and the lack of pain associated with c.8B6 provide a rationale for the future clinical application of c.8B6 in high-risk NBL patients.…”

Antitumor and cytotoxic properties of a humanized antibody specific for the GM3(Neu5Gc) ganglioside

“…ADCC has been described as one of the effector mechanisms associated with antibodies against tumor-associated gangliosides (Chapman et al, 1990;Fukumoto et al, 1999;Terme et al, 2014;Yamada et al, 2011). It was previously reported that high concentrations of mouse 14F7 mAb were required to induce ADCC in GM3(Neu5Gc)-expressing P3 × 63 cells.…”

TargetingO-Acetyl-GD2 Ganglioside for Cancer Immunotherapy

“…However, ADCC is considered as an important clinical mechanism for anti-GD2 immunotherapy [102, 103]. In this respect, anti- O -acetyl-GD2 mAbs seem to be particularly effective as compared to anti-GD2 antibodies in mediating ADCC against O -acetyl-GD2-expressing tumor cells [39, 87, 104]. We also found that anti- O -acetyl-GD2 mAb antibodies induce significant CDC in addition to ADCC in vitro [39].…”

“…The precise mechanisms by which antibodies specific for O -acetyl-GD2 trigger tumor cell death still require clarification. While they seem to be influenced by O -acetyl-GD2 density at the tumor cell surface, they are also influenced by the antibody isotype [104] similarly to anti-GD2 mAbs [83]. Thus, the proapoptotic activity of anti- O -acetyl-GD2 mAbs cannot be fully explained by their sole antigen recognition activity.…”

“…To facilitate clinical development of therapeutic antibodies targeting O -acetyl-GD2, our group also developed a mouse/human IgG1 chimeric version of antibody 8B6 [104]. The chimeric IgG1 c.8B6 antibody was obtained from the mouse mAb 8B6 to O -acetyl-GD2 and expressed in CHO-S cells.…”