P1, N=70, Not yet recruiting, Aptamer Sciences, Inc.

P1, N=140, Recruiting, BeiGene | Not yet recruiting --> Recruiting

P1, N=179, Active, not recruiting, Chugai Pharmaceutical | Recruiting --> Active, not recruiting

P1/2, N=81, Recruiting, Boston Pharmaceuticals, Inc. | Not yet recruiting --> Recruiting

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.

P1, N=48, Recruiting, Myeloid Therapeutics | Not yet recruiting --> Recruiting

P1, N=48, Not yet recruiting, Myeloid Therapeutics

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.

P1, N=40, Recruiting, Second Affiliated Hospital of Guangzhou Medical University | Trial primary completion date: Dec 2025 --> Dec 2029

P2, N=30, Recruiting, Eureka Therapeutics Inc. | Trial completion date: Dec 2027 --> Dec 2026

P2, N=24, Recruiting, Eureka Therapeutics Inc. | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2024 --> Dec 2026

P2, N=24, Recruiting, Eureka Therapeutics Inc. | Phase classification: P1/2 --> P2

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.

P1, N=179, Recruiting, Chugai Pharmaceutical | Trial completion date: Sep 2024 --> Dec 2025 | Trial primary completion date: Sep 2024 --> Dec 2025

P1/2, N=24, Recruiting, Eureka Therapeutics Inc. | Trial completion date: Jul 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024 | N=12 --> 24

P1, N=20, Recruiting, Shanghai Ming Ju Biotechnology Co., Ltd.

P1/2, N=106, Recruiting, Sanofi | Trial completion date: May 2030 --> Dec 2030 | Trial primary completion date: May 2030 --> Dec 2030

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.

P1, N=20, Recruiting, Shanghai Ming Ju Biotechnology Co., Ltd.

P1, N=9, Recruiting, Newish Technology (Beijing) Co., Ltd.

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.

P1/2, N=81, Not yet recruiting, Boston Pharmaceuticals, Inc.

Conclusions These preliminary results from the first two DLs suggest that SAR444200 is tolerable at the tested DLs in patients with advanced solid tumors. Dose escalation continues at this time.

P1, N=50, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P1/2, N=106, Recruiting, Sanofi | Trial completion date: May 2029 --> May 2030 | Trial primary completion date: May 2029 --> May 2030

In vivo, CYT-303 showed no toxicity or cytokine release in cynomolgus monkeys up to the highest dose (60 mg/kg), administered weekly by intravenous infusion for 28 days. These results demonstrate the potential of CYT-303 to be a safe and effective therapy against HCC.

CYT-303 efficacious doses identified in the HCC model together with safety in cynomolgus monkeys and planned human pharmacokinetic modeling studies support clinical evaluation of CYT-303 in first in human HCC clinical trials.

SENTI-301A is a novel off-the-shelf preclinical CAR-NK cell therapy candidate that targets GPC3-expressing tumors in an antigen-specific manner and exhibits increased persistence via crIL-15. We are exploring the potential synergy between SENTI-301A and CPIs to enhance the existing antitumor functions of SENTI-301A. SENTI-301A is planned for clinical development with an investigational new drug application (IND) expected in 2023.

This work demonstrates that KI of IL-15 and KO of TGFβR2 is a promising strategy for TALEN®-engineered iNK cell therapies to overcome the immunosuppressive TME and mount a potent and persistent anti-tumor immune response. The data also provide a solid foundation for combining these edited iNK cells with CYT-303 to address the immunosuppressive TME towards a cure for HCC.

The superagonistic monoclonal anti-human CD28 antibody (IgG4κ) TGN1412 was used as comparator. Activity is maintained while it allows well tailorable dose response with reduced cytokine release. Compounds are currently in extensive pre-clinical assessment 999

GPC3 cleavage in hepatoblastoma (HB) has a role in cell proliferation with therapeutic potential, however furin inhibition is not an appropriate target for GPC3-expressing HB due to increased migration which may enhance metastatic potential.

GPC3 expression is frequent in MCC tumors, especially MCPyV-negative cases, and is associated with increased risk of death. High prevalence of surface GPC3 makes it a putative drug target.

Conclusions Pharmacologically active CYT-303 doses were identified. CYT-303 can help recruit NK cells to the tumor site to achieve tumor growth inhibition.

P1/2, N=92, Recruiting, Keymed Biosciences Co.Ltd | Not yet recruiting --> Recruiting

Although both conjugates were comparably effective in their radiolabeling efficiencies, [Ac]Ac-GC33-BZmacropa showed slightly poorer serum stability and biodistribution than [Ac]Ac-GC33-macropa. Together, these results establish HBZmacropa-NCS as a new bifunctional chelator for the preparation of Ac radiopharmaceuticals.

miR-4510 may change the immunosuppressive signals in the tumor microenvironment by downregulating GPC3 and inhibiting gastric cancer cell metastasis. Oxaliplatin treatment may become a specific therapeutic drug for patients with miR-4510 inhibition and GPC3-GC.

GPC3 has a high prevalence in selected tumors with low level expression in some normal tissues, making it an attractive target for CAR T cell therapy. The GC33 clone performs similarly to 1G12 and could be used for IHC screening for CAR T cell therapy. MRCLS has higher prevalence of GPC3+ expression relative to other LS subtypes.

The iCAR-ILC-N101 is an allogeneic human leukocyte antigen (HLA)-homozygous induced pluripotent stem cell (iPSC)-derived anti-glypican-3 (GPC3) CAR-expressing innate lymphoid cells/natural killer cell (ILC/NK), which has both antigen-specific and NK activating receptor-mediated cytotoxicity...No dose-limiting toxicity was observed. Clinical trial registry number: jRCT2033200431

CYT-303 greatly enhanced the cytotoxic activity of iNKs and cytolysis of Hep3B tumor cells in-vitro. CYT-303 and iNK cells, alone or in combination, demonstrate anti-tumor activity against HCC that warrants clinical development.