A GPC2 antibody-drug conjugate is efficacious against neuroblastoma and small-cell lung cancer via binding a conformational epitope

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 cancer...

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Published in:Cell reports. Medicine 2021-07, Vol.2 (7), p.100344, Article 100344
Main Authors: Raman, Swetha, Buongervino, Samantha N, Lane, Maria V, Zhelev, Doncho V, Zhu, Zhongyu, Cui, Hong, Martinez, Benjamin, Martinez, Daniel, Wang, Yanping, Upton, Kristen, Patel, Khushbu, Rathi, Komal S, Navia, Carmen T, Harmon, Daniel B, Li, Yimei, Pawel, Bruce, Dimitrov, Dimiter S, Maris, John M, Julien, Jean-Philippe, Bosse, Kristopher R
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Animals
antibody-drug conjugate
Bystander Effect - drug effects
Cell Compartmentation
Cell Death - drug effects
Cell Membrane - metabolism
DNA Damage
Epitopes - chemistry
Epitopes - metabolism
Female
glypican
Glypicans - immunology
Humans
Immunoconjugates - pharmacology
Lung Neoplasms - pathology
Mice
Mice, Inbred C57BL
Mice, SCID
MYCN
N-Myc Proto-Oncogene Protein - metabolism
neuroblastoma
Neuroblastoma - pathology
Oncogene Proteins - metabolism
Protein Conformation
Small Cell Lung Carcinoma - pathology
small-cell lung cancer
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Summary: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 Å 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 toxicity. These studies provide preclinical data to support the clinical translation of ADCs targeting GPC2.
ISSN:2666-3791
2666-3791
DOI:10.1016/j.xcrm.2021.100344