A Monoclonal Antibody to O-Acetyl-GD2 Ganglioside and Not to GD2 Shows Potent Anti-Tumor Activity without Peripheral Nervous System Cross-Reactivity

Abstract

BackgroundMonoclonal antibodies (mAb) against GD2 ganglioside have been shown to be effective for the treatment of neuroblastoma. Beneficial actions are, however, associated with generalized pain due to the binding of anti- GD2 mAbs to peripheral nerve fibers followed by complement activation. Neuroblastoma cells that express GD2 also express its O-acetyl derivative, O-acetyl- GD2 ganglioside (OAcGD2). Hence, we investigated the distribution of OAcGD2 in human tissues using mAb 8B6 to study the cross-reactivity of mAb 8B6 with human tissues.Methodology/Principal FindingsThe distribution of OAcGD2 was performed in normal and malignant tissues using an immunoperoxydase technique. Anti-tumor properties of mAb 8B6 were studied in vitro and in vivo in a transplanted tumor model in mice. We found that OAcGD2 is not expressed by peripheral nerve fibers. Furthermore, we demonstrated that mAb 8B6 was very effective in the in vitro and in vivo suppression of the growth of tumor cells. Importantly, mAb 8B6 anti-tumor efficacy was comparable to that of mAb 14G2a specific to GD2.Conclusion/SignificanceDevelopment of therapeutic antibodies specific to OAcGD2 may offer treatment options with reduced adverse side effects, thereby allowing dose escalation of antibodies.

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

“…O-acetyl-GD2 (OAc-GD2) is a naturally occurring GD2 derivative that is highly expressed on the surface of GD2 positive tumor cells, somewhat comparable to GD2 on those tumor cells [81,82]. Appealingly, unlike GD2, OAc-GD2 appears to not be expressed on peripheral nerves.…”

“…Therefore, targeting this antigen might reduce the neuropathic pain associated with anti-GD2 mAb therapy while retaining antitumor efficacy. 8B6 is an anti-OAc-GD2 mAb with no cross reaction to GD2 [82,83]. When compared with 14.G2a, 8B6 demonstrates comparable epitope binding affinity and in vitro suppression of tumor growth [82].…”

“…8B6 is an anti-OAc-GD2 mAb with no cross reaction to GD2 [82,83]. When compared with 14.G2a, 8B6 demonstrates comparable epitope binding affinity and in vitro suppression of tumor growth [82]. In animal models, 8B6 is as efficient but better tolerated than 14.G2a, highlighting the potential use of this mAb to avoid anti-GD2 associated neuropathic side effects [82].…”

Universal Artificial Antigen Presenting Cells to Selectively Propagate T Cells Expressing Chimeric Antigen Receptor Independent of Specificity

“…The synthesis of DNA plasmid GD2G4CAR (Figure S1.B), specific to sphingolipid GD2, utilized the same 19G4CAR backbone. The GD2-specific scFv derived from murine mAb (clone 14G2a) 21 was commercially synthesized (Geneart, Life Technologies) as codon-optimized cDNA with Nhe I and Xmn I restriction enzyme (RE) sites flanking the scFv. The 19G4CAR plasmid backbone and GD2-specific scFv cDNA were excised using these REs and ligated to replace CD19-specific scFv with GD2-specific scFv.…”

Targeting of tumor-associated gangliosides with antibodies affects signaling pathways and leads to cell death including apoptosis

“…Prominent examples include overexpression of GM2, fucosyl-GM1 in small cell lung cancer (SCLC), GD3 in melanoma, GD2 in neuroblastoma and some sarcomas [19][20][21][22]. Moreover, GD2, GD3, GT3 gangliosides containing O-acetyl-N-acetylneuraminic acid or GM3 containing N-glycolylneuraminic acid can be detected [23,24]. Alterations of gangliosides content can be related to tumor aggressiveness, clinical behavior, and modulated by therapeutic agents.…”