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Combination Therapy of Hepatocellular Carcinoma by GPC3-Targeted Bispecific Antibody and Irinotecan is Potent in Suppressing Tumor Growth in Mice.

ABSTRACT: Hepatocellular carcinoma (HCC) is a world leading cause of cancer-related mortality, and currently no curative treatment for advanced HCC is available. Glypican-3 (GPC3) is an attractive target for HCC immunotherapy. This study explored the efficacy of six GPC3-targeted bispecific antibodies, alone or in combination with chemotherapeutic drug Irinotecan, for the treatment of HCC. The bispecific antibodies were constructed using three different structures, knob-into-hole (KH), scFv-scFv-hFc, and scFv-hFc-scFv, where CD3-targeting mAb OKT3 (scFv) was paired with two representative GPC3 mAbs hYP7 (scFv) and HN3 (VH only) that target different epitopes. The In vitro cell killing assay revealed that all bispecific antibodies efficiently killed GPC3 positive cancer cells, with hYP7-KH, hYP7-OKT3-hFc, and HN3-KH being most potent. In vivo xenograft mouse studies demonstrated that all bispecific antibodies suppressed tumor growth similarly, with hYP7-OKT3-hFc performing slightly better. Combination of hYP7-OKT3-hFc with Irinotecan dramatically improved the efficacy and arrested tumor growth of HepG2, Hep3B, and G1 in xenograft mice. Our results demonstrated that the cell surface proximal bispecific antibody hYP7-OKT3-hFc was superior in terms of potency and the GPC3-targeted bispecific antibody combined with Irinotecan was much potent to control HCC growth.

SUBMITTER: Chen X

PROVIDER: S-EPMC8742776 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Combination Therapy of Hepatocellular Carcinoma by GPC3-Targeted Bispecific Antibody and Irinotecan is Potent in Suppressing Tumor Growth in Mice.

Chen Xin X Chen Yanmin Y Liang Rong R Xiang Lanxin L Li Jingwen J Zhu Yuankui Y He Huixia H Huang Le L Zuo Dianbao D Li Weihang W Liang Xinjun X Dong Shuang S Hu Sheng S Ho Mitchell M Feng Mingqian M

Molecular cancer therapeutics 20211101 1

Hepatocellular carcinoma (HCC) is a world leading cause of cancer-related mortality, and currently no curative treatment for advanced HCC is available. Glypican-3 (GPC3) is an attractive target for HCC immunotherapy. This study explored the efficacy of six GPC3-targeted bispecific antibodies, alone or in combination with chemotherapeutic drug Irinotecan, for the treatment of HCC. The bispecific antibodies were constructed using three different structures, knob-into-hole (KH), scFv-scFv-hFc, and ...[more]

PMID: 34725191

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Project description:PurposeHepatocellular carcinoma (HCC) remains one of the most challenging diseases worldwide. Glypican-3 (GPC-3) is a cell surface proteoglycan that is overexpressed on the membrane of HCC cells. The purpose of this study was to develop a target-specific radiofluorinated peptide for positron emission tomography (PET) imaging of GPC3 expression in hepatocellular carcinoma.ProceduresNew GPC3-binding peptides (GP2076 and GP2633) were radiolabeled with F-18 using Al[18F]F labeling approach, and the resulting PET probes were subsequently subject to biological evaluations. A highly hydrophilic linker was incorporated into GP2633 with an aim of reducing the probe uptake in liver and increasing tumor-to-liver (T/L) contrast. Both GP2076 and GP2633 were radiolabeled using Al[18F]F chelation approach. The binding affinity, octanol/water partition coefficient, cellular uptake and efflux, and stability of both F-18 labeled peptides were tested. Tumor targeting efficacy and biodistribution of Al[18F]F-GP2076 and Al[18F]F-GP2633 were determined by PET imaging in HCC-bearing mice. Immunohistochemistry analyses were performed to compare the findings from PET scans.ResultsAl[18F]F-GP2076 and Al[18F]F-GP2633 were rapidly radiosynthesized within 20 min in excellent radiochemical purity (> 97 %). Al[18F]F-GP2633 was determined to be more hydrophilic than Al[18F]F-GP2076 in terms of octanol/water partition coefficient. Both Al[18F]F-GP2076 and Al[18F]F-GP2633 demonstrated good in vitro and in vivo stability and binding specificity to GPC3-positive HepG2 cells. For PET imaging, Al[18F]F-GP2633 exhibited enhanced uptake in HepG2 tumor (%ID/g 3.37 ± 0.35 vs. 2.13 ± 0.55, P = 0.031) and reduced accumulation in liver (%ID/g 1.70 ± 0.26 vs. 3.70 ± 0.98, P = 0.027) at 60 min post-injection (pi) as compared to Al[18F]F-GP2076, resulting in significantly improved tumor-to-liver (T/L) contrast (ratio 2.00 ± 0.18 vs. 0.59 ± 0.14, P = 0.0004). Higher uptake of Al[18F]F-GP2633 in GPC3-positive HepG2 tumor was observed as compared to GPC3-negative McA-RH7777 tumor (%ID/g 3.37 ± 0.35 vs. 1.64 ± 0.03, P = 0.001) at 60 min pi, confirming GPC3-specific accumulation of Al[18F]F-GP2633 in HepG2 tumor.ConclusionThe results demonstrated that Al[18F]F-GP2633 is a promising probe for PET imaging of GPC3 expression in HCC. Convenient preparation, excellent GPC3 specificity in HCC, and favorable excretion profile of Al[18F]F-GP2633 warrant further investigation for clinical translation. PET imaging with a GPC3-specific probe would provide clinicians with vital diagnostic information that could have a significant impact on the management of HCC patients.

Dataset Information

Combination Therapy of Hepatocellular Carcinoma by GPC3-Targeted Bispecific Antibody and Irinotecan is Potent in Suppressing Tumor Growth in Mice.

Publications

Combination Therapy of Hepatocellular Carcinoma by GPC3-Targeted Bispecific Antibody and Irinotecan is Potent in Suppressing Tumor Growth in Mice.

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