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

Swetha Raman; Samantha N Buongervino; Maria V Lane; Doncho V Zhelev; Zhongyu Zhu; Hong Cui; Benjamin Martinez; Daniel Martinez; Yanping Wang; Kristen Upton; Khushbu Patel; Komal S Rathi; Carmen T Navia; Daniel B Harmon; Yimei Li; Bruce Pawel; Dimiter S Dimitrov; John M Maris; Jean-Philippe Julien; Kristopher R Bosse

doi:10.1016/j.xcrm.2021.100344

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

Cell Rep Med. 2021 Jul 21;2(7):100344. doi: 10.1016/j.xcrm.2021.100344. eCollection 2021 Jul 20.

Authors

Swetha Raman¹, Samantha N Buongervino², Maria V Lane², Doncho V Zhelev³, Zhongyu Zhu⁴, Hong Cui¹, Benjamin Martinez¹, Daniel Martinez⁵, Yanping Wang⁴, Kristen Upton², Khushbu Patel², Komal S Rathi⁶, Carmen T Navia⁷, Daniel B Harmon⁷, Yimei Li⁸, Bruce Pawel^{9

10}, Dimiter S Dimitrov³, John M Maris^{2

11}, Jean-Philippe Julien^{1

12}, Kristopher R Bosse^{2

11}

Affiliations

¹ Program in Molecular Medicine, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.
² Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
⁴ Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA.
⁵ Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁶ Department of Biomedical and Health Informatics and Center for Data-Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁷ Integral Molecular, Philadelphia, PA 19104, USA.
⁸ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁹ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
¹⁰ Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
¹¹ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
¹² Departments of Biochemistry and Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.

Abstract

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. These studies provide preclinical data to support the clinical translation of ADCs targeting GPC2.

Keywords: MYCN; antibody-drug conjugate; glypican; neuroblastoma; small-cell lung cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Bystander Effect / drug effects
Cell Compartmentation
Cell Death / drug effects
Cell Membrane / metabolism
DNA Damage
Epitopes / chemistry*
Epitopes / metabolism*
Female
Glypicans / immunology*
Humans
Immunoconjugates / pharmacology*
Lung Neoplasms / pathology*
Mice
Mice, Inbred C57BL
Mice, SCID
N-Myc Proto-Oncogene Protein / metabolism
Neuroblastoma / pathology*
Oncogene Proteins / metabolism
Protein Conformation
Small Cell Lung Carcinoma / pathology*

Substances

Epitopes
Glypicans
Immunoconjugates
MYCN protein, human
N-Myc Proto-Oncogene Protein
Oncogene Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding