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

Chen, Xin; Chen, Yanmin; Liang, Rong; Xiang, Lanxin; Li, Jingwen; Zhu, Yuankui; He, Huixia; Huang, Le; Zuo, Dianbao; Li, Weihang; Liang, Xiaofeng; Dong, Shuang; Hu, Sheng; Ho, Mitchell; Feng, Mingqian

doi:10.1158/1535-7163.mct-20-1025

Cited by 8 publications

(4 citation statements)

References 53 publications

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“…The choice of HEPG2 cells to assess the impact of gamma irradiation and paclitaxel on in vitro ADP-ribosyl transferase activity of PE24 moiety was based on the fact that HEPG2 cells are known for their high chemotherapeutic and radiotherapy resistance. Recent research was dedicated to generating ITs harnessing PE24 to combat chemo/radio-resistant HEPG2 cells (Chen et al 2022;Heiat et al 2021). For this reason, HEPG2 cells were used while exploring the impact of gamma radiation and paclitaxel on PE24 moiety.…”

Section: Discussionmentioning

confidence: 99%

Gamma radiation coupled ADP-ribosyl transferase activity of Pseudomonas aeruginosa PE24 moiety

Morgan

Saleh

Farrag

et al. 2023

Appl Microbiol Biotechnol

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The ADP-ribosyl transferase activity of P. aeruginosa PE24 moiety expressed by E. coli BL21 (DE3) was assessed on nitrobenzylidene aminoguanidine (NBAG) and in vitro cultured cancer cell lines. Gene encoding PE24 was isolated from P. aeruginosa isolates, cloned into pET22b( +) plasmid, and expressed in E. coli BL21 (DE3) under IPTG induction. Genetic recombination was confirmed by colony PCR, the appearance of insert post digestion of engineered construct, and protein electrophoresis using sodium dodecyl-sulfate polyacrylamide gel (SDS-PAGE). The chemical compound NBAG has been used to confirm PE24 extract ADP-ribosyl transferase action through UV spectroscopy, FTIR, c13-NMR, and HPLC before and after low-dose gamma irradiation (5, 10, 15, 24 Gy). The cytotoxicity of PE24 extract alone and in combination with paclitaxel and low-dose gamma radiation (both 5 Gy and one shot 24 Gy) was assessed on adherent cell lines HEPG2, MCF-7, A375, OEC, and Kasumi-1 cell suspension. Expressed PE24 moiety ADP-ribosylated NBAG as revealed by structural changes depicted by FTIR and NMR, and the surge of new peaks at different retention times from NBAG in HPLC chromatograms. Irradiating recombinant PE24 moiety was associated with a reduction in ADP-ribosylating activity. The PE24 extract IC50 values were < 10 μg/ml with an acceptable R2 value on cancer cell lines and acceptable cell viability at 10 μg/ml on normal OEC. Overall, the synergistic effects were observed upon combining PE24 extract with low-dose paclitaxel demonstrated by the reduction in IC50 whereas antagonistic effects and a rise in IC50 values were recorded after irradiation by low-dose gamma rays. Key points • Recombinant PE24 moiety was successfully expressed and biochemically analyzed. • Low-dose gamma radiation and metal ions decreased the recombinant PE24 cytotoxic activity. • Synergism was observed upon combining recombinant PE24 with low-dose paclitaxel.

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Section: Discussionmentioning

confidence: 99%

Gamma radiation coupled ADP-ribosyl transferase activity of Pseudomonas aeruginosa PE24 moiety

Morgan

Saleh

Farrag

et al. 2023

Appl Microbiol Biotechnol

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“…In some cases, the epitope may be more important than affinity. Similar studies on GPC3-targeted immunotherapy demonstrated that bispecific antibody that targets the C-terminal had stronger potency (35), while immunotoxins target the N-terminal of GPC3 had stronger potency (36).…”

Section: Discussionmentioning

confidence: 87%

Strengthening of antitumor effects in breast cancer from a novel B7-H4- and CD3-targeting bispecific antibody by an oncolytic virus

Tang¹,

Ma²,

Chen³

et al. 2022

Ann Transl Med

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Background: For programmed cell death protein 1/programmed death-ligand 1 (PD-L1)-positive triplenegative breast cancer (TNBC), the addition of immune checkpoint inhibitors (ICIs) to chemotherapy has been shown to increase the objective response rate (ORR) by only 13.4-16.3%. Thus, examining converting tumor immunogenicity and targeting novel pathways may be needed to improve response to immunotherapy. B7-H4 is an emerging target for breast cancer immunotherapy. However, the antitumor effect of B7-H4 is unstable during cell generation and further research is necessary to strengthen the antitumor efficacy of B7-H4.Methods: To explore the potential of B7-H4-targeted immunotherapy of breast cancer, current study generated four monoclonal antibodies (mAbs) against B7-H4 through immunization of mice followed by phage display technology. T cell-engaged bispecific antibodies and immunotoxins were created based on these mAbs. To evaluate the anti-tumor activity of B7-H4-targeting bispecific antibody and immunotoxin, the anti-tumor efficacy test in vitro and in mice models in vivo were performed. Moreover, to boost the efficacy, oncolytic virus herpes simplex virus type 2 (HSV-2) was combined with the bispecific antibody and tested in mice models.Results: Rigorous in vitro cytotoxicity assay showed that both B7-H4 bispecific antibodies and immunotoxins were toxic to B7-H4 positive cells, with the former being more potent. However, in vivo studies showed that immunotoxin was slightly more effective in suppressing tumor growth. Further, bispecific antibody combined with oncolytic virus HSV-2 revealed a synergistic effect in suppressing tumor growth without causing obvious adverse effects.Conclusions: Collectively, our findings uncover a novel strategy of combining oncolytic virus HSV-2 with bispecific antibody reinforce antitumor immune response, which warranted further translational investigation.

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“…The same group of potential targets mentioned above can again be considered in this case. Bispecific antibodies targeting GPC3 have shown activity in xenograft mice [84]. ERY974 is a bispecific antibody that engages CD3 on T cells and GPC3 on tumor cells that underwent a phase I trial in patients with any GPC3-positive solid tumor type.…”

Section: Bispecific Antibodiesmentioning

confidence: 99%

Recent Progress in Systemic Therapy for Advanced Hepatocellular Carcinoma

Sadagopan,

2024

IJMS

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Patients with advanced hepatocellular carcinoma (HCC) have several systemic treatment options. There are many known risk factors for HCC, and although some, such as hepatitis C, are now treatable, others are not. For example, metabolic dysfunction-related chronic liver disease is increasing in incidence and has no specific treatment. Underlying liver disease, drug resistance, and an increasing number of treatment options without specific biomarkers are all challenges in selecting the best treatment for each patient. Conventional chemotherapy is almost never used for advanced-stage disease, which instead is treated with immunotherapy, tyrosine kinase inhibitors, and VEGF inhibitors. Immune checkpoint inhibitors targeting various receptors have been or are currently undergoing clinical evaluation. Ongoing trials with three-drug regimens may be the future of advanced-stage HCC treatment. Other immune-modulatory approaches of chimeric antigen receptor-modified T cells, bispecific antibodies, cytokine-induced killer cells, natural killer cells, and vaccines are in early-stage clinical trials. Targeted therapies remain limited for HCC but represent an area of potential growth. As we shift away from first-line sorafenib for advanced HCC, clinical trial control arms should comprise a standard treatment other than sorafenib, one that is a better comparator for advancing therapies.

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

Cited by 8 publications

References 53 publications

Gamma radiation coupled ADP-ribosyl transferase activity of Pseudomonas aeruginosa PE24 moiety

Gamma radiation coupled ADP-ribosyl transferase activity of Pseudomonas aeruginosa PE24 moiety

Strengthening of antitumor effects in breast cancer from a novel B7-H4- and CD3-targeting bispecific antibody by an oncolytic virus

Recent Progress in Systemic Therapy for Advanced Hepatocellular Carcinoma

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