6WJL

Crystal structure of Glypican-2 core protein in complex with D3 Fab

Summary for 6WJL

• Entry DOI: 10.2210/pdb6wjl/pdb
• Descriptor: Glypican-2, D3 Fab Heavy chain, VHH domain, ... (4 entities in total)
• Functional Keywords: neuroblastoma, oncoprotein, proteoglycan, therapeutic antibody, oncoprotein-immune system complex, oncoprotein/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 223432.67

Authors

Raman, S.,Maris, J.M.,Bosse, K.R.,Julien, J.P. (deposition date: 2020-04-14, release date: 2021-04-21, Last modification date: 2024-10-30)

Primary citation

Raman, S.,Buongervino, S.N.,Lane, M.V.,Zhelev, D.V.,Zhu, Z.,Cui, H.,Martinez, B.,Martinez, D.,Wang, Y.,Upton, K.,Patel, K.,Rathi, K.S.,Navia, C.T.,Harmon, D.B.,Li, Y.,Pawel, B.,Dimitrov, D.S.,Maris, J.M.,Julien, J.P.,Bosse, K.R.
A GPC2 antibody-drug conjugate is efficacious against neuroblastoma and small-cell lung cancer via binding a conformational epitope.
Cell Rep Med, 2:100344-100344, 2021

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

PubMed: 34337560
DOI: 10.1016/j.xcrm.2021.100344

Experimental method

X-RAY DIFFRACTION (3.3 Å)