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Updated: Jan 16, 2026
A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
Published on: July 12, 2018
Antibody-gamma/delta T cell receptors targeting GPC2 regress neuroblastoma with low antigen density
Alex Quan1, Mingyu Huo1, Dan Li1
1Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
Abstract:
Chimeric antigen receptor (CAR) T cells have shown promise in hematological cancers but face challenges in solid tumors, partly due to heterogeneous antigen density. Glypican-2 (GPC2) is an oncofetal antigen highly expressed in neuroblastoma and under evaluation in phase 1 clinical trials. Here, we engineer T cells with antibody-T cell receptors (AbTCRs) targeting GPC2. We generate autologous AbTCR T cells using CT3 or humanized CT3 (hCT3) antigen-binding fragments (Fab) linked to γ/δ T cell receptors (TCRs), along with a CD30 co-stimulatory domain. Both CT3 and hCT3 AbTCR T cells show superior antitumor efficacy compared to CT3 CAR T cells, with hCT3 AbTCR T cells inducing significant regression in neuroblastoma with low GPC2 antigen density. Enhanced efficacy is associated with stronger TCR signaling, expansion of stem cell-like memory T cells, and improved CD8+ T cell infiltration. These results highlight the potential of hCT3 AbTCR T cells for neuroblastoma and indicate broad application of AbTCR T cells in solid tumors.
Insights
New antibody-T cell receptors (AbTCRs) targeting Glypican-2 (GPC2) show promise for neuroblastoma. Humanized CT3 AbTCR T cells effectively treat tumors with low GPC2 antigen density, outperforming CAR T cells.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR) T cells show efficacy in blood cancers but struggle with solid tumors due to antigen heterogeneity.
- Glypican-2 (GPC2) is a promising target for neuroblastoma, with increasing clinical evaluation.
- Novel T cell engineering strategies are needed to overcome challenges in solid tumor immunotherapy.
Purpose of the Study:
- To engineer and evaluate antibody-T cell receptors (AbTCRs) targeting GPC2 for enhanced neuroblastoma treatment.
- To compare the efficacy of GPC2-targeting AbTCR T cells against conventional GPC2-targeting CAR T cells.
- To investigate the mechanisms underlying AbTCR T cell activity in solid tumors.
Main Methods:
- Generation of autologous AbTCR T cells using CT3 or humanized CT3 (hCT3) antigen-binding fragments (Fab) linked to γ/δ T cell receptors (TCRs) and a CD30 co-stimulatory domain.
- In vivo efficacy studies in neuroblastoma models with varying GPC2 antigen densities.
- Analysis of T cell signaling, memory cell expansion, and immune cell infiltration.
Main Results:
- Both CT3 and hCT3 AbTCR T cells demonstrated superior antitumor efficacy compared to CT3 CAR T cells.
- hCT3 AbTCR T cells induced significant tumor regression in neuroblastoma models, even with low GPC2 antigen density.
- Enhanced efficacy correlated with increased TCR signaling, expansion of stem cell-like memory T cells, and improved CD8+ T cell infiltration.
Conclusions:
- hCT3 AbTCR T cells represent a promising therapeutic strategy for neuroblastoma, particularly in cases with heterogeneous GPC2 expression.
- AbTCR T cell technology holds potential for broader application in treating various solid tumors.
- This study underscores the advantage of AbTCRs over CARs in overcoming antigen density challenges in solid tumor immunotherapy.
