Highly Potent Immunotoxins Targeting the Membrane-distal N-lobe of GPC3 for Immunotherapy of Hepatocellular Carcinoma

Li, Jingwen; Xiang, Lanxin; Wang, Qian; Ma, Xuqian; Chen, Xin; Zhu, Yuankui; Yang, Yaxi; Huang, Le; He, Huixia; Xu, Lilei; Liang, Xiaofeng; Dong, Shuang; Hu, Sheng; Li, Hanjie; Feng, Mingqian

doi:10.7150/jca.66978

Cited by 6 publications

(3 citation statements)

References 42 publications

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“…Previous studies have revealed that PE24 caused the modification of eukaryotic elongation factor-2 and induced cell death by apoptosis or pyroptosis. 13,40,41 In our studies, we noted that the dying cells triggered by T22-PE24 showed evident cell swelling and giant bubbles from the plasma membrane (Fig. 3E), which are the typical characteristics of pyroptosis.…”

Section: Resultsmentioning

confidence: 61%

A self-assembling CXCR4-targeted pyroptosis nanotoxin for melanoma therapy

et al. 2023

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Section: Resultsmentioning

confidence: 61%

A self-assembling CXCR4-targeted pyroptosis nanotoxin for melanoma therapy

et al. 2023

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“…Furthermore, these tumor cell membrane proteins were either highly expressed in tumors or prognostic risk factors for tumor patients. Furthermore, some of them have been proven to be drug targets in solid tumors, such as GPC3 in liver cancer [ 36 ], MSLN in gastric cancer, and EGFR in glioma ( Figure 2 D).…”

Section: Resultsmentioning

confidence: 99%

Pan-Cancer Analysis Identifies Tumor Cell Surface Targets for CAR-T Cell Therapies and Antibody Drug Conjugates

Zhou

Zhang

et al. 2022

Cancers

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Tumor cells can be recognized through tumor surface antigens by immune cells and antibodies, which therefore can be used as drug targets for chimeric antigen receptor-T (CAR-T) therapies and antibody drug conjugates (ADCs). In this study, we aimed to identify novel tumor-specific antigens as targets for more effective and safer CAR-T cell therapies and ADCs. Here, we performed differential expression analysis of pan-cancer data obtained from the Cancer Genome Atlas (TCGA), and then performed a series of conditional screenings including Cox regression analysis, Pearson correlation analysis, and risk-score calculation to find tumor-specific cell membrane genes. A tumor tissue-specific and highly expressed gene set containing 3919 genes from 17 cancer types was obtained. Moreover, the prognostic roles of these genes and the functions of these highly expressed membrane proteins were assessed. Notably, 427, 584, 431 and 578 genes were identified as risk factors for LIHC, KIRC, UCEC, and KIRP, respectively. Functional enrichment analysis indicated that these tumor-specific surface proteins might confer tumor cells the ability to invade and metastasize. Furthermore, correlation analysis displayed that most overexpressed membrane proteins were positively correlated to each other. In addition, 371 target membrane protein-coding genes were sifted out by excluding proteins expressed in normal tissues. Apart from the identification of well-validated genes such as GPC3, MSLN and EGFR in the literature, we further confirmed the differential protein expression of 23 proteins: ADD2, DEF6, DOK3, ENO2, FMNL1, MICALL2, PARVG, PSTPIP1, FERMT1, PLEK2, CD109, GNG4, MAPT, OSBPL3, PLXNA1, ROBO1, SLC16A3, SLC26A6, SRGAP2, and TMEM65 in four types of tumors. In summary, our findings reveal novel tumor-specific antigens, which could be potentially used for next-generation CAR-T cell therapies and ADC discovery.

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“…When tumor formed and reached a volume of 100-200 mm 3 , mice were randomly divided into different treatment groups according to the mean tumor volume, with ve mice each group. Treatment of mice was accomplished by intratumoral injections of EGFRvIII Immunotoxin R6-PE24, and GPC3-targeted immunotoxin HN3-PE24, which was previously generated in our lab [30], was served as a control. Tumor dimensions were measured by Vernier calipers every 2 to 3 days.…”

Section: Subcutaneous Xenograft Mouse Modelmentioning

confidence: 99%

EGFRvIII-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma

Huang

Wang

et al. 2022

Preprint

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Purpose: EGFRvⅢ is an established target for immunotherapy of glioblastoma (GBM). Current study aims to explore the efficacy of EGFRvⅢ-targeted immunotoxin combined with temozolomide (TMZ) or T cell-engaged bispecific antibody for the treatment of GBM.Methods: We generated three rabbit monoclonal antibodies (R1, R2, and R6) that specifically bound to EGFRvⅢ, but not EGFR, with high affinity. Immunotoxins were made by fusing the scFv of these antibodies with engineered Pseudomonas exotoxin PE24. The in vitro cytotoxicity and specificity of the immunotoxins was rigorously validated by EGFRvIII and EGFR-expressed cell lines. The in vivo efficacy of immunotoxin monotherapy and in combination with TMZ or EGFRvⅢ-targeted bispecific antibody was evaluated in orthotopic and subcutaneous xenograft mouse models.Results: EGFRvIII immunotoxins potently killed U87, U251 and GL261 cells that were forcefully expressing EGFRvIII, with IC50 values bellow 1.2 ng/ml. In a subcutaneous model, multiple intratumoral injections of immunotoxin at a dose of 2 mg/kg resulted in complete tumor regression in 3/5 of mice. In a C57BL/6 orthotopic glioma model transplanted with GL261 cells that expressed a mouse version of EGFRvIII, two injections of 10 micrograms of immunotoxin in the lateral ventricles significantly improved the survival, with 2/5 mice being completely cured. Furthermore, in a subcutaneous xenograft model transplanted with EGFRvIII-expressed U87 cells, a single intratumoral injection of immuntoxin followed by i.v. injections of TMZ or EGFRvⅢ-targeted bispecific antibody achieved complete regression in mice.Conclusion: EGFRvIII immunotoxins combined TMZ or T cell-engaged bispecific antibody offers promise for curative treatment of GBM.

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Highly Potent Immunotoxins Targeting the Membrane-distal N-lobe of GPC3 for Immunotherapy of Hepatocellular Carcinoma

Cited by 6 publications

References 42 publications

A self-assembling CXCR4-targeted pyroptosis nanotoxin for melanoma therapy

A self-assembling CXCR4-targeted pyroptosis nanotoxin for melanoma therapy

Pan-Cancer Analysis Identifies Tumor Cell Surface Targets for CAR-T Cell Therapies and Antibody Drug Conjugates

EGFRvIII-targeted immunotoxin combined with temozolomide and bispecific antibody for the eradication of established glioblastoma

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