Novel cucurmosin‐based immunotoxin targeting programmed cell death 1‐ligand 1 with high potency against human tumor in vitro and in vivo

Zhang, Caiyun; Xiong, Jiani; Lan, Yinxiang; Wu, Jingyu; Wang, Chengyan; Huang, Zhihong; Lin, Jizhen; Xie, Jing

doi:10.1111/cas.14549

Cited by 11 publications

(6 citation statements)

References 43 publications

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“…Results of the cytotoxicity assay in vitro showed that the killing ability of Bs/CUS on different tumor cells was time-dependent under the conditions of 72 and 120 h incubation. This result and incubation time are consistent with the research results of other immunotoxins using CUS as a toxic agent in our laboratory ( 28 , 29 ).…”

Section: Discussionsupporting

confidence: 92%

Novel EGFR‑bispecific recombinant immunotoxin based on cucurmosin shows potent anti‑tumor efficiency in vitro

et al. 2020

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Epidermal growth factor receptor (EGFR) is overexpressed in various tumors and is associated with cancer initiation, progression, and poor prognosis. Despite the achievements made by tyrosine kinase inhibitors and monoclonal antibodies in certain cases, many patients have not benefited from such treatment due to resistance. Immunotoxins (ITs) are antibody-cytotoxin chimeric molecules with specific cell killing ability, which have achieved different degrees of success in the treatment of a wide range of cancers in clinical trials. The aim of the current study was to examine a novel targeting EGFR recombinant immunotoxin Bs/cucurmosin (CUS) generated by fusing CUS to the EGFR-specific nanobody 7D12-9G8. Bs/CUS was successfully expressed in Escherichia coli strain BL21 (DE3) in a soluble form. Furthermore, it retained binding capacity and specificity with EGFR and was superior to rE/CUS, a monospecific IT we reported previously. In vitro results showed that Bs/CUS could be internalized into the cytoplasm and selectively kill cells in the picomolar range. Flow cytometry showed that Bs/CUS killed the cells mediated by the apoptosis pathway. Taken together, results of the current study indicated that Bs/CUS is a promising candidate that should be further evaluated as a cancer therapeutic for the treatment of EGFR-positive tumors.

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Section: Discussionsupporting

confidence: 92%

Novel EGFR‑bispecific recombinant immunotoxin based on cucurmosin shows potent anti‑tumor efficiency in vitro

et al. 2020

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“…Moreover, according to our research, the inhibition might be caused by DVL and thus further increases the drug sensitivity of DTX. The advantages of our HSA-DTX@PEG-DVL NPs in terms of cytotoxicity might be mainly due to cellular uptake superiority and synergy between DVL and DTX, much of the literature also suggested that finding. − Consequently, we have shown that the combination of the anticancer drugs DTX and DVL in a single nanoplatform significantly reduces tumor cell progression compared to each drug alone. As a result, our findings suggested that the addition of the DVL mAb on HSA-DTX@PEG-DVL NPs loaded with DTX is a better solution for anticancer efficacy.…”

Section: Discussionmentioning

confidence: 71%

Synthesis and Optimization of the Docetaxel-Loaded and Durvalumab-Targeted Human Serum Albumin Nanoparticles, In Vitro Characterization on Triple-Negative Breast Cancer Cells

et al. 2023

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Triple-negative breast cancer (TNBC) tends to behave more aggressively compared to other breast cancer subtypes due to the lack of receptors and its limited targeting therapy. In recent years, nanotechnology advancement has led to the development of various nanoparticle platforms for the targeted treatment of cancers. Especially, HSA-NPs have specific advantages such as biocompatibility, adjustable size during production, and relatively easy synthesis. In this study, HSA-NPs were encapsulated with docetaxel (DTX) and functionalized with polyethylene glycol (PEG), also becoming a targeting nanoplatform modified with durvalumab (DVL), and the whole nanostructure was well characterized. Subsequently, drug release studies and various in vitro cell culture studies such as determining the cytotoxicity and apoptotic levels of the nanoplatforms and PD-L1 using ELISA test were conducted on MDA-MB-468, MDA-MB-231, and MCF-7 cells. According to the results, HSA-DTX@PEG-DVL NPs showed better cytotoxicity compared to DTX in all the three cell lines. In addition, it was observed that the HSA-DTX@PEG-DVL NPs did not lead the cells to late apoptosis but were effective in the early apoptotic stage. Moreover, the ELISA data showed a significantly induced PD-L1 expression due to the presence of DVL in the nanostructure, which indicates that DVL antibodies successfully bind to the HSA-DTX@PEG-DVL nanostructure.

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“…Interestingly, the principle of a PD-L1 targeting immunotoxin, based on cucurmosin, has been demonstrated by Zhang et al [51]. As saporin used in our study, cucurmosin is also a type I ribosome-inactivating protein (RIP) that potently inhibits protein synthesis but lacks an effective mechanism to enter cytosol upon endocytosis [52].…”

Section: Discussionmentioning

confidence: 82%

Light-controlled elimination of PD-L1+ cells

Wong

Selbo

2021

Preprint

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The programmed death ligand-1 (PD-L1), also known as CD274 or B7-H1, is mainly expressed on cancer cells and/or immunosuppressive cells in the tumor microenvironment (TME) and plays an essential role in tumor progression and immune escape. Immune checkpoint inhibitors (ICIs) of the PD-1/PD-L1 axis have shown impressive clinical success, however, the majority of the patients do not respond to immune checkpoint therapy (ICT). Thus, to overcome ICT resistance there is a high need for potent and novel strategies that simultaneously target both tumor cells and immunosuppressive cells in the TME. In this study, we show that the intracellular light-controlled drug delivery method photochemical internalization (PCI) induce specific and strongly enhanced cytotoxic effects of the PD-L1-targeting immunotoxin, anti-PD-L1-saporin (Anti-PDL1-SAP), in the PD-L1+ triple-negative breast cancer MDA-MB-231 cell line, while no enhanced efficacy was obtained in the PD-L1 negative control cell line MDA-MB-453. Using fluorescence microscopy, we reveal that the anti-PD-L1 antibody binds to PD-L1 on the surface of the MDA-MD-231 cells and overnight accumulates in late endosomes and lysosomes where it co-localizes with the PCI photosensitizer fimaporfin (TPCS2a). Moreover, light-controlled endosomal/lysosomal escape of the anti-PD-L1 antibody and fimaporfin into the cytosol was obtained. We also confirm that the breast MDA-MB-468 and the prostate PC-3 and DU-145 cancer cell lines have subpopulations with PD-L1 expression. In addition, we show that interferon-gamma strongly induce PD-L1 expression in the per se PD-L1 negative CT26.WT cells and enhance the PD-L1 expression in MC-38 cells, of which both are murine colon cancer cell lines. In conclusion, our work provides an in vitro proof-of-concept of PCI-enhanced targeting and eradication of PD-L1 positive immunosuppressive cells. This light-controlled combinatorial strategy has a potential to advance cancer immunotherapy and should be explored in preclinical studies.

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Novel cucurmosin‐based immunotoxin targeting programmed cell death 1‐ligand 1 with high potency against human tumor in vitro and in vivo

Cited by 11 publications

References 43 publications

Novel EGFR‑bispecific recombinant immunotoxin based on cucurmosin shows potent anti‑tumor efficiency in vitro

Novel EGFR‑bispecific recombinant immunotoxin based on cucurmosin shows potent anti‑tumor efficiency in vitro

Synthesis and Optimization of the Docetaxel-Loaded and Durvalumab-Targeted Human Serum Albumin Nanoparticles, In Vitro Characterization on Triple-Negative Breast Cancer Cells

Light-controlled elimination of PD-L1+ cells

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