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

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.

doi:10.1016/j.xcrm.2021.100344

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

Journal Article · 30 June 2021 · Cell Reports Medicine

DOI: https://doi.org/10.1016/j.xcrm.2021.100344 · OSTI ID:1816158

Raman, Swetha ^[1]; 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.

Edgewater Federal Solutions/OSTI

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 in vivo toxicity. Furthermore, these studies provide preclinical data to support the clinical translation of ADCs targeting GPC2.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1816158

Journal Information:: Cell Reports Medicine, Journal Name: Cell Reports Medicine Journal Issue: 7 Vol. 2; ISSN 2666-3791

Publisher:: Cell PressCopyright Statement

Country of Publication:: United States

Language:: English

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Related Subjects

60 APPLIED LIFE SCIENCES
MYCN
antibody-drug conjugate
glypican
neuroblastoma
small-cell lung cancer

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

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