Glypican-3-Targeted Alpha Particle Therapy for Hepatocellular Carcinoma

Abstract

Glypican-3 (GPC3) is expressed in 75% of hepatocellular carcinoma (HCC), but not normal liver, making it a promising HCC therapeutic target. GC33 is a full-length humanized monoclonal IgG1 specific to GPC3 that can localize to HCC in vivo. GC33 alone failed to demonstrate therapeutic efficacy when evaluated in patients with HCC; however, we posit that cytotoxic functionalization of the antibody with therapeutic radionuclides, may be warranted. Alpha particles, which are emitted by radioisotopes such as Actinium-225 (Ac-225) exhibit high linear energy transfer and short pathlength that, when targeted to tumors, can effectively kill cancer and limit bystander cytotoxicity. Macropa, an 18-member heterocyclic crown ether, can stably chelate Ac-225 at room temperature. Here, we synthesized and evaluated the efficacy of [225Ac]Ac–Macropa–GC33 in mice engrafted with the GPC3-expressing human liver cancer cell line HepG2. Following a pilot dose-finding study, mice (n = 10 per group) were treated with (1) PBS, (2) mass-equivalent unmodified GC33, (3) 18.5 kBq [225Ac]Ac–Macropa–IgG1 (isotype control), (4) 9.25 kBq [225Ac]Ac–Macropa–GC33, and (5) 18.5 kBq [225Ac]Ac–Macropa–GC33. While significant toxicity was observed in all groups receiving radioconjugates, the 9.25 kBq [225Ac]Ac–Macropa–GC33 group demonstrated a modest survival advantage compared to PBS (p = 0.0012) and 18.5 kBq [225Ac]Ac–IgG1 (p = 0.0412). Hematological analysis demonstrated a marked, rapid reduction in white blood cells in all radioconjugate-treated groups compared to the PBS and unmodified GC33 control groups. Our studies highlight a significant disadvantage of using directly-labeled biomolecules with long blood circulation times for TAT. Strategies to mitigate such treatment toxicity include dose fractionation, pretargeting, and using smaller targeting ligands.

Immunotherapy Updates in Advanced Hepatocellular Carcinoma

“…Anti-GPC-3 CAR-T cells have demonstrated powerful cytotoxic responses in HCC cell lines and in vivo experiments. Clinical trials using anti-GPC-3 CAR-T cells are currently ongoing [ 61 , 62 , 63 ].…”

Glypican 3 (GPC 3) In Cancer Pathogenesis and Progression

“…In HCC tumours originating from tissues which express GPC 3 only in the embryo, GPC 3 expression tend to turn up with malignant transformation [52]. Because GPC 3 is strongly expressed in embryonic liver, downregulated in the normal adult liver and overexpressed/re-expressed in HCC, these results suggest that GPC 3 behaves as an oncofetal protein in these tissues [53]. Oncofetal proteins may be useful as tumour markers or as immunotherapy targets [2,54].…”

Novel Nanotechnology Approaches to Overcome Drug Resistance in the Treatment of Hepatocellular Carcinoma: Glypican 3 as a Useful Target for Innovative Therapies

“…GC33 has been exploited for radiotherapy coupled with the radionuclide actinium-225 to synthesize the radioconjugate [ 225 Ac]Ac-Macropa-GC33 [ 172 ]. HepG2 tumor-bearing mice were treated with two dosages of radioconjugate and tumor delay was observed.…”

“…HepG2 tumor-bearing mice were treated with two dosages of radioconjugate and tumor delay was observed. However, significant toxicities have also been detected in all treated mice, suggesting the need for optimization in the activity amount and administration [ 172 ]. An antibody targeting GPC3 has been used as radioconjugate with 227 Th(NO 3 ) 4 to synthetize 227 Th-octapa-αGPC3 [ 173 ].…”