Therapeutic activity of the non-internalizing antibody drug conjugate 1959-sss/DM3 targeting galectin3-binding protein in human neuroblastoma

Abstract Neuroblastoma is a solid tumour affecting the peripheral nervous system accounting for ∼13% of all pediatric cancer mortality. Despite immunotherapy with the GD2 antibody has improved the clinical outcome of a fraction of patients with metastatic neuroblastoma, the majority of patients with relapsing, high risk disease cannot be successfully treated. Recently, it has been shown that non-internalizing, linker-less antibody drug conjugates (ADCs) targeting the tumor extracellular environment can exert a potent therapeutic activity against different tumors. We identified LGALS3BP (aka Mac-2 BP or 90K) as an important target for non-internalizing ADC development, as the protein is largely secreted by the majority of human tumors, while being virtually undetectable in normal adult tissues. In this study, we show that a variant of the humanized 1959 antibody, targeting human LGALS3BP, coupled to the maytansinoid drugs DM3 by means of disulfide linker, bound human neuroblastoma cell lines harboring or not N-myc amplification, although with different affinity. Importantly, normal human fibroblasts were not decorated by the antibody. The ADC potently inhibited metastatic lesions in the liver and lungs of NSG mice injected intravenously with the neuroblastoma cell line SKNAS. Our findings offer a preclinical proof-of-concept for the development of a non-internalizing ADC endowed with potent therapeutic activity for neuroblastoma treatment through an innovative mechanism of action. Citation Format: Emily Capone, Sara Ponziani, Francesco Giansanti, Roberta Gentile, Giulia Di Vittorio, Vincenzo De Laurenzi, Michele Sallese, Sandra Bibbò, Arturo Sala, Rodolfo Ippoliti, Jean Frederic Sauniere, Stefano Iacobelli, Gianluca Sala. Therapeutic activity of the non-internalizing antibody drug conjugate 1959-sss/DM3 targeting galectin3-binding protein in human neuroblastoma [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 238.