codrituzumab (RG7686)

First-in-human studies, including 124I-codrituzumab and 68Ga-RAYZ-8009, confirmed tumor-specific accumulation but remained limited in scale...The available evidence suggests a preferential pathway, involving the selection of a limited set of lead vectors, their pairing with suitable radionuclides, validation in orthotopic/PDX models using standardized endpoints, and the integration of comprehensive dosimetric and toxicologic studies before proceeding to broader human trials. GPC3-directed theranostics thus offers a compelling, disease-specific route to precision management of HCC, provided translational rigor addresses the outlined safety and quantitative imaging gaps.

Furthermore, the GPC3 CRISPR-Cas9@UPSND treatment exhibits superior anti-proliferative efficacy in tumor-growth prevention compared to Codrituzumab, as evidenced by the analysis of Ki67 and GPC3 expression, along with serum GPC3 levels. These findings underscore the translational potential of the non-viral UPSND nanoplatform-based CRISPR GPC3 genome editing, offering a promising targeted therapeutic strategy for HCC treatment.

Meanwhile, hGC33-OMVs suppressed HepG2 cell proliferation, induced G1-phase arrest, and reduced Wnt3a, β-catenin, Cyclin D1, and C-myc expression. Engineered E. coli hGC33-OMVs effectively target HCC via the hGC33-GPC3 interaction, inhibit tumor growth by suppressing Wnt signaling, and demonstrate potential for use as a versatile platform for antibody delivery.

Recent clinical trials have demonstrated that ADCs targeting GPC3, such as GC33 and 32A9, show promising results in reducing tumor growth and improving patient outcomes in advanced HCC...The exclusion criteria included languages other than English and publications before 2019. A total of 26 articles were identified, and 12 articles were selected after quality assessment.

P1, N=50, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Jun 2025 --> Jun 2026

To enhance their action, a targeting agent, such as the humanized anti-GPC3 antibody GC33 (condrituzumab), could be attached to their surface. In HUH7 tumor-bearing xenograft mice, CS-NBs loaded with idarubicin and conjugated or not conjugated with 4A1 were both able to slow tumor growth, to increase mouse survival time compared to free idarubicin (p = 0.00044 and 0.0018, respectively) as well as to reduce drug side effects. CS-NBs loaded with idarubicin can be a useful drug delivery strategy for HCC treatment.

To confirm the usefulness of the models for GPC3-targeted drug development, we evaluated the target engagement of a GPC3-selective antibody, GC33, conjugated to the positron-emitting zirconium-89 (89Zr) in subcutaneous murine xenografts of wild type (WT) and KO liver cancer cell lines...KO lines demonstrated increased sensitivity to ERK (GDC09994), while AKT (MK2206) inhibition was more effective in WT lines...We show that GPC3-KO liver cancer cell lines exhibit decreased tumorigenicity and altered signaling pathways, including upregulated pMAPK/ERK1/2, compared to parental lines. Furthermore, we successfully distinguished between GPC3+ and GPC3- tumors using the GPC3-targeted immunoPET imaging agent, demonstrating the potential utility of these cell lines in facilitating GPC3-selective drug development.

The Hbp-hGC 33-OMVs prepared in this study demonstrated stronger ability of binding to Hep G2 cells than the wild-type OMVs (P=0.008). All the data indicated that Hbp-hGC 33-OMVs with anti-GPC3 single-chain antibody were successfully prepared and could be used for research on the targeted therapy of hepatocellular carcinoma.

Finally, the combination of microwave ablation with GC33-G2D-NK cell administration showed greater CAR-NK infiltration and tumor regression in ablated tumors than monotherapy alone. These findings indicate that administration of GPC3-CAR-NK cells may be a potential strategy for the treatment of HCC, and regional delivery or their combination with microwave ablation may optimize their efficacy against HCC and may have translational value.

FFPE slides were stained for GPC3+ (GC33, Ventana), PD-L1+ (22C3, Dako) cells and then scanned at 20x using the Aperio Versa8 scanner... Here we profiled GPC3 expression across tumor types and showed high level of expression in HCC followed by SQ-NSCLC. We have established an AI-powered digital pathology platform that can provide a standardized, scalable, and reproducible method of characterizing GPC3 positivity to support further patient selection in clinical study.

VAM generated from the cellular plasma membrane was bio-synthetically fabricated, with the recombinant protein (hGC33 scFv-melittin) being harbored and displayed on the cell membrane...Nanomelittin formed pores in membranes and disturbed phospholipid bilayers, which allowed the anticancer agents (i.e., chemotherapeutic drug doxorubicin and sonosensitizer purpurin 18 nanoparticles) co-delivered by VAM to penetrate deeper tumor sites, leading to synergistic therapeutic effects. In particular, the punching effect generated by sonodynamic therapy further improved the immunomodulatory effect of nanomelittin to activate the immune response. Taken together, our findings indicate that clinically translatable VAM-based strategies represent a universal, promising approach to multimodal synergetic cancer therapy.

GC33, a humanized mAb directed against GPC3, is a safe and well-tolerated therapy choice for patients with HCC, which tested in a phase I trial in advanced HCC patients...CD16A activation and increased cytokines release were associated with higher anti-tumor activity. In conclusion, this bispecific antibody may possibly help develop new therapeutic strategies for HCC and develop new treatment options in the future.