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Crystal structure of Glypican-2 core protein in complex with D3 Fab
Structural highlights
FunctionGPC2_HUMAN Cell surface proteoglycan that bears heparan sulfate. May fulfill a function related to the motile behaviors of developing neurons (By similarity). Publication Abstract from PubMedGlypican 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 A 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. A GPC2 antibody-drug conjugate is efficacious against neuroblastoma and small-cell lung cancer via binding a conformational epitope.,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, Bosse KR Cell Rep Med. 2021 Jul 21;2(7):100344. doi: 10.1016/j.xcrm.2021.100344. , eCollection 2021 Jul 20. PMID:34337560[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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