期刊
CELL REPORTS MEDICINE
卷 2, 期 7, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.xcrm.2021.100344
关键词
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资金
- Damon Runyon Cancer Research Foundation [PST-07-16]
- St. Baldrick's-Stand Up to Cancer Dream Team Transla-tional Research Grant [SU2C-AACR-DT-27-17]
- Alex's Lemonade Stand Foundation
- Hyundai Hope on Wheels Young Investigator Award
- NCI [K08 CA230223, U54 CA232568, R35 CA220500]
- Giulio D'Angio Endowed Chair
- EVAN Foundation
- CIFAR Azrieli Global Scholar program
- Canada Research Chairs program [950231604]
- National Cancer Institute [ACB-12002]
- National Institute of General Medical Sciences [AGM-12006]
- NIH Office of Research Infrastructure Programs, High-End Instrumentation [S10 OD012289]
- DOE Office of Science [DE-AC02-06CH11357]
GPC2 is a MYCN-regulated oncoprotein that is highly expressed in neuroblastoma and small-cell lung cancers (SCLCs), making it a potential target for immune-based therapies and ADCs. Studies have shown that the GPC2-directed ADC can induce durable tumor regression in neuroblastoma and SCLC by inducing DNA damage, apoptosis, and bystander cell killing, with no signs of in vivo toxicity.
Glypican 2 (GPC2) is a MYCN-regulated, differentially expressed cell-surface oncoprotein and target for immune-based therapies in neuroblastoma. Here, we build on GPC2's immunotherapeutic attributes by finding that it is also a highly expressed, MYCN-driven oncoprotein on small-cell lung cancers (SCLCs), with significantly enriched expression in both the SCLC and neuroblastoma stem cell compartment.By solving the crystal structure of the D3-GPC2-Fab/GPC2 complex at 3.3 A resolution, we further illustrate that the GPC2-directed antibody-drug conjugate (ADC; D3-GPC2-PBD), that links a human GPC2 antibody (D3) to DNA damaging pyrrolobenzodiazepine (PBD) dimers, binds a tumor-specific, conformation-dependent epitope of the core GPC2 extracellular domain. We then show that this ADC induces durable neuroblastoma and SCLC tumor regression via induction of DNA damage, apoptosis, and bystander cell killing, notably with no signs of ADC-induced in vivo toxicity. These studies provide preclinical data to support the clinical translation of ADCs targeting GPC2.
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