Related Experiment Video
Updated: Oct 26, 2025
A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
Published on: July 12, 2018
A GPC2 antibody-drug conjugate is efficacious against neuroblastoma and small-cell lung cancer via binding a
Swetha Raman1, Samantha N Buongervino2, Maria V Lane2
1Program in Molecular Medicine, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, 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.
Insights
Glypican 2 (GPC2) is a target for neuroblastoma and small-cell lung cancer (SCLC) therapies. An antibody-drug conjugate targeting GPC2 effectively reduced tumors in preclinical models without toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Glypican 2 (GPC2) is a MYCN-regulated oncoprotein found on neuroblastoma cells, making it a potential target for immunotherapy.
- GPC2 expression is also identified in small-cell lung cancer (SCLC) and enriches within the stem cell compartments of both SCLC and neuroblastoma.
Purpose of the Study:
- To investigate the potential of GPC2 as a therapeutic target in SCLC.
- To characterize the binding and efficacy of a GPC2-directed antibody-drug conjugate (ADC).
Main Methods:
- Crystal structure determination of the D3-GPC2-Fab/GPC2 complex.
- Development and testing of a GPC2-specific ADC (D3-GPC2-PBD) comprising a GPC2 antibody and a DNA-damaging agent.
- Evaluation of ADC efficacy in preclinical neuroblastoma and SCLC models, assessing tumor regression, DNA damage, apoptosis, and bystander effects.
Main Results:
- The crystal structure revealed that the D3 antibody binds a specific epitope on the GPC2 extracellular domain.
- The D3-GPC2-PBD ADC demonstrated durable tumor regression in both neuroblastoma and SCLC models.
- ADC treatment induced DNA damage and apoptosis, leading to significant tumor regression and bystander cell killing.
- No significant in vivo toxicity was observed with the GPC2-targeted ADC.
Conclusions:
- GPC2 is a promising therapeutic target for both neuroblastoma and SCLC, particularly within the cancer stem cell populations.
- GPC2-targeted ADCs, such as D3-GPC2-PBD, show significant preclinical efficacy and a favorable safety profile.
- These findings support the clinical translation of GPC2-targeting ADCs for treating neuroblastoma and SCLC.
More Related Videos
11:58Initial Evaluation of Antibody-conjugates Modified with Viral-derived Peptides for Increasing Cellular Accumulation and Improving Tumor Targeting
Published on: March 8, 2018
11:02Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018