Thomas Maria, Nguyen Thu Hien, Drnevich Jenny, D'Souza Amber M, de Alarcon Pedro A, Gnanamony Manu
Department of Pediatrics, University of Illinois College of Medicine Peoria, One Illini Drive, Peoria, IL 61605, USA.
Roy J. Carver Biotechnology Center, The University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801, USA.
Cancers (Basel). 2024 May 30;16(11):2064. doi: 10.3390/cancers16112064.
The disialoganglioside, GD2, is a promising therapeutic target due to its overexpression in certain tumors, particularly neuroblastoma (NB), with limited expression in normal tissues. Despite progress, the intricate mechanisms of action and the full spectrum of the direct cellular responses to anti-GD2 antibodies remain incompletely understood. In this study, we examined the direct cytotoxic effects of the humanized anti-GD2 antibody hu14.18K322A (hu14) on NB cell lines, by exploring the associated cell-death pathways. Additionally, we assessed the synergy between hu14 and conventional induction chemotherapy drugs. Our results revealed that hu14 treatment induced direct cytotoxic effects in CHLA15 and SK-N-BE1 cell lines, with a pronounced impact on proliferation and colony formation. Apoptosis emerged as the predominant cell-death pathway triggered by hu14. Furthermore, we saw a reduction in GD2 surface expression in response to hu14 treatment. Hu14 demonstrated synergy with induction chemotherapy drugs with alterations in GD2 expression. Our comprehensive investigation provides valuable insights into the multifaceted effects of hu14 on NB cells, shedding light on its direct cytotoxicity, cell-death pathways, and interactions with induction chemotherapy drugs. This study contributes to the evolving understanding of anti-GD2 antibody therapy and its potential synergies with conventional treatments in the context of NB.
双唾液酸神经节苷脂GD2是一个很有前景的治疗靶点，因为它在某些肿瘤中过度表达，尤其是神经母细胞瘤（NB），而在正常组织中表达有限。尽管取得了进展，但抗GD2抗体的复杂作用机制以及对其直接细胞反应的全貌仍未完全了解。在本研究中，我们通过探索相关的细胞死亡途径，研究了人源化抗GD2抗体hu14.18K322A（hu14）对NB细胞系的直接细胞毒性作用。此外，我们评估了hu14与传统诱导化疗药物之间的协同作用。我们的结果显示，hu14处理在CHLA15和SK-N-BE1细胞系中诱导了直接细胞毒性作用，对增殖和集落形成有显著影响。凋亡是由hu14触发的主要细胞死亡途径。此外，我们发现hu14处理后GD2表面表达降低。Hu14与诱导化疗药物表现出协同作用，且伴有GD2表达的改变。我们的全面研究为hu14对NB细胞的多方面作用提供了有价值的见解，揭示了其直接细胞毒性、细胞死亡途径以及与诱导化疗药物的相互作用。这项研究有助于深化对抗GD2抗体治疗及其在NB背景下与传统治疗潜在协同作用的理解。
