Abstract 543: Dinutuximab binds specifically to disialoganglioside-2

Abstract

Abstract Dinutuximab is a human/murine chimeric monoclonal antibody, approved for maintenance treatment of pediatric patients with high-risk neuroblastoma (NB) in the US, and currently under investigation in a phase III trial (NCT03098030) for 2nd line treatment of relapsed/refractory small cell lung cancer (SCLC). Despite four decades of development, the specificity of dinutuximab binding to its intended target, disialoganglioside-2 (GD2), has not been fully elucidated. Although GD2 is a relatively cancer cell specific antigen, other cell surface gangliosides are ubiquitously expressed on the outer membrane of healthy human cells. Therefore, the main goal of this study was to confirm binding specificity of dinutuximab to GD2. We also compared relative affinity of dinutuximab to GD2 with 14G2a, which is the original murine anti-GD2 antibody from which dinutuximab was derived. To measure dinutuximab and 14G2a binding kinetics to various relevant gangliosides (GD1a, GD1b, GM3, GD3, GM4, GM2 and GD2), an in vitro assay was developed and optimized using the Biacore surface plasmon resonance platform. The results showed that GD2 was the only ganglioside that binds to dinutuximab (relative KD=0.000337M). The relative affinity of GD2 to dinutuximab and 14G2a antibody were comparable and within 2-fold of each other (Table). In conclusion, dinutuximab specifically binds to GD2. The absence of binding to GM3, GD3, GD1a, or GD1b suggests that an exposed N-acetylgalactosamine (GalNAc) moiety is necessary for antibody recognition. The absence of binding to GM2 or GT2 (sugar moiety), which differ from GD2 by the number of sialic residues attached to the basal galactose moiety, suggests that the number of sialic acid residues is also critical for antibody recognition. GD2 binding kinetics of Dinutuximab and 14G2aLigandKD (M)ka (1/Ms)kd (1/s)Chi2 (RU2)Dinutuximab3.37E-042.48E+028.34E-020.78614G2a2.00E-047.11E+021.42E-010.0273 Citation Format: Shahriar Yaghoubi, Travis Harrison, Gerald Messerschmidt, Suzana Corritori. Dinutuximab binds specifically to disialoganglioside-2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 543.