Bispecific GD2xB7-H3 Antibody Improves Tumor Targeting and Reduces Toxicity while Maintaining Efficacy for Neuroblastoma
Erbe, A.; Feils, A.; Reinthaler, S.; Hampton, A.; Rosenkrans, Z.; Medina Guevara, Y.; Felder, M.; Wiwczar, J.; Gerhardt, D.; Bercher, M.; Wenke, B.; Haertle, C.; Heck, M.; Heimstreet, K.; Frankel, E.; Nielsen, M.; Spiegelman, D.; Tsarovsky, N.; Zaborek, J.; Rakhmilevich, A.; Hank, J.; Aluicio-Sarduy, E.; Engle, J.; Davis, J.; Glaser, B.; Subbotin, V.; Green, R.; Hernandez, R.; Hammer, B.; Sondel, P.
Show abstract
The current treatment regimen for neuroblastoma involves immunotherapy, including a monoclonal antibody that recognizes disialoganglioside (GD2), expressed at high levels on neuroblastoma. GD2 is not present on most normal tissues except for nerves. Thus, anti-GD2 antibody treatment causes substantial, dose-limiting neuropathic pain. B7-H3 is overexpressed on multiple tumor types, including neuroblastoma, and is largely absent on nerves and other normal tissues. We designed a bispecific antibody (bsAb) that requires simultaneous binding of these two tumor antigens to achieve tight binding of tumor cells. Our preclinical research shows that, compared with a monospecific anti-GD2 antibody, the GD2xB7-H3 bsAb has improved tumor specificity, comparable antitumor efficacy, and reduced nerve binding and pain-associated toxicity. Since this bsAb does not bind to nerves, it may permit more tolerable and sustained treatment schedules than are currently feasible with monospecific anti-GD2 antibodies. In addition, its enhanced tumor specificity may support future development as a targeted delivery platform for antibody-drug conjugates or other payload-based therapies, potentially improving both efficacy and quality of life for patients with neuroblastoma.
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