Identification and Preclinical Evaluation of a Novel GD2 Antibody-Drug Conjugate for Solid Tumors in Children and Adults.
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The ganglioside GD2 is an attractive cancer target because of its high expression in neuroblastoma and other solid tumors with limited normal-tissue distribution. Despite regulatory approvals of three anti-GD2 antibodies, clinical efficacy remains limited by neurotoxicity, suboptimal affinity for antibody-dependent cellular cytotoxicity (ADCC), and immunogenicity. Developing a highly effective, less toxic anti-GD2 agent remains an unmet need. In this study, a novel anti-GD2 murine antibody, CA450, was identified by immunizing mice with GD2 conjugated to keyhole limpet hemocyanin or Qβ virus-like particles, followed by phage display screening. The humanized version, hCA450-21, displayed higher cell-binding activity than ch14.18 and Hu3F8, along with excellent specificity and internalization capacity. To overcome the limitations of traditional anti-GD2 antibody therapy, hCA450-21 was engineered and conjugated to exatecan to create an antibody-drug conjugate (ADC), which may reduce or avoid neurotoxicity by employing a mechanism distinct from ADCC and complement-dependent cytotoxicity. The hCA450-21.1-LA-68B ADC demonstrated potent in vitro cytotoxicity against glioblastoma, melanoma, and breast cancer cell lines and in vivo tumor growth inhibition in LN229 and SK-MEL-5 xenograft models. Toxicity studies in mice showed a favorable safety profile, with reduced neurotoxicity compared with naked antibody therapy by ch14.18-IgG1 and hCA450-21.1-IgG1. The crystal structure of the hCA450-21.1 Fab-GD2 complex was resolved at 1.69 Å, revealing unique hydrogen bonds and hydrophobic interactions that contribute to its high specificity and affinity. Overall, the novel hCA450-21.1-LA-68B ADC shows preclinical efficacy and reduced toxicity, particularly neurotoxicity, indicating potential as a safer and more effective therapy for GD2-positive pediatric and adult tumors.