Neuroblastoma is the most common extracranial solid tumor in children. Approximately 45% of patients receiving standard therapy relapse and ultimately succumb to metastatic disease. One of the major challenges in the treatment of neuroblastoma and other pediatric cancers is the lack of effective targets. As such, there is an urgent need for a new therapeutic target. Here we demonstrate that glypican-2 (GPC2) protein is highly expressed in nearly half of neuroblastoma cases. High GPC2 expression has been correlated with poor overall survival when compared to patients with low GPC2 expression. The reduction of GPC2 expression inhibits neuroblastoma cell growth and induces tumor cell apoptosis through downregulation of Wnt/β-catenin signaling. We have discovered a group of human single domain antibodies specific for GPC2 and have used them to make two forms of antibody therapeutics, antibody-toxin conjugates (immunotoxins) and chimeric antigen receptor (CAR) T cells. Treatment with the immunotoxin inhibits proliferation of GPC2-positive neuroblastoma cells in vitro and mouse models. The CAR T cells targeting GPC2 suppress the growth of neuroblastoma xenograft tumors and eradicate disseminated neuroblastomas in mice. Our study establishes GPC2 as a new target of antibody-based cancer therapy and demonstrates that single domain-based antibody therapeutics can be used in the treatment of neuroblastoma.

Citation Format: Nan Li, Haiying Fu, Stephen Hewitt, Dimiter Dimitrov, Javed Khan, Mitchell Ho. Targeting glypican-2 in neuroblastoma via single domain antibody-based immunotoxins and chimeric antigen receptor T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3648. doi:10.1158/1538-7445.AM2017-3648