1. A GPC2 antibody-drug conjugate is efficacious against neuroblastoma and small-cell lung cancer via binding a conformational epitope.
- Author
-
Raman S, Buongervino SN, Lane MV, Zhelev DV, Zhu Z, Cui H, Martinez B, Martinez D, Wang Y, Upton K, Patel K, Rathi KS, Navia CT, Harmon DB, Li Y, Pawel B, Dimitrov DS, Maris JM, Julien JP, and Bosse KR
- Subjects
- Animals, Bystander Effect drug effects, Cell Compartmentation, Cell Death drug effects, Cell Membrane metabolism, DNA Damage, Female, Humans, Mice, Inbred C57BL, Mice, SCID, N-Myc Proto-Oncogene Protein metabolism, Oncogene Proteins metabolism, Protein Conformation, Mice, Epitopes chemistry, Epitopes metabolism, Glypicans immunology, Immunoconjugates pharmacology, Lung Neoplasms pathology, Neuroblastoma pathology, Small Cell Lung Carcinoma pathology
- 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., Competing Interests: D.V.Z., Z.Z., D.S.D., J.M.M., and K.R.B. hold patents for the discovery and development of immunotherapies for cancer, including patents related to GPC2-directed immunotherapies. K.R.B. and J.M.M. receive research funding from Tmunity for research on GPC2-directed immunotherapies, and D.V.Z., Z.Z., D.S.D., J.M.M., and K.R.B. receive royalties from Tmunity for licensing of GPC2-related intellectual property., (© 2021 The Authors.)
- Published
- 2021
- Full Text
- View/download PDF