A Novel Bispecific Antibody Targeting CD3 and Lewis Y with Potent Therapeutic Efficacy against Gastric Cancer

Chen, Jie; Pan, Zhidi; Han, Lei; Zhou, Yuexian; Zong, Huifang; Wang, Lei; Sun, Rui; Jiang, Hua; Xie, Yueqing; Yuan, Yunsheng; Wu, Mingyuan; Bian, Yanling; Zhang, Baohong; Zhu, Jianwei

doi:10.3390/biomedicines9081059

Cited by 18 publications

(10 citation statements)

References 49 publications

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“…HEK 293F cells were transiently transfected with plasmids loading antibody genes and cultured. The supernatant containing anti Nectin-4 antibody was collected for antibody extraction and purification as previously described [ 37 ].…”

Section: Methodsmentioning

confidence: 99%

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer

et al. 2022

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Background Triple-negative breast cancer (TNBC) is more prone to distant metastasis and visceral recurrence in comparison to other breast cancer subtypes, and is related to dismal prognosis. Nevertheless, TNBC has an undesirable response to targeted therapies. Therefore, to tackle the huge challenges in the diagnosis and treatment of TNBC, Nectin-4 was selected as a theranostic target because it was recently found to be highly expressed in TNBC. We developed anti-Nectin-4 monoclonal antibody (mAbNectin-4)-based theranostic pair, 99mTc-HYNIC-mAbNectin-4 and mAbNectin-4-ICG. 99mTc-HYNIC-mAbNectin-4 was applied to conduct immuno-single photon emission computed tomography (SPECT) for TNBC diagnosis and classification, and mAbNectin-4-ICG to mediate photothermal therapy (PTT) for relieving TNBC tumor growth. Methods Nectin-4 expression levels of breast cancer cells (MDA-MB-468: TNBC cells; and MCF-7, non-TNBC cells) were proved by western blot, flow cytometry, and immunofluorescence imagning. Cell uptake assays, SPECT imaging, and biodistribution were performed to evaluate Nectin-4 targeting of 99mTc-HYNIC-mAbNectin-4. A photothermal agent (PTA) mAbNectin-4-ICG was generated and characterized. In vitro photothermal therapy (PTT) mediated by mAbNectin-4-ICG was conducted under an 808 nm laser. Fluorescence (FL) imaging was performed for mAbNectin-4-ICG mapping in vivo. In vivo PTT treatment effects on TNBC tumors and corresponding systematic toxicity were evaluated. Results Nectin-4 is overexpressed in MDA-MB-468 TNBC cells, which could specifically uptake 99mTc-HYNIC-mAbNectin-4 with high targeting in vitro. The corresponding immunoSPECT imaging demonstrated exceptional performance in TNBC diagnosis and molecular classification. mAbNectin-4-ICG exhibited favourable biocompatibility, photothermal effects, and Nectin-4 targeting. FL imaging mapped biodistribution of mAbNectin-4-ICG with excellent tumor-targeting and retention in vivo. Moreover, mAbNectin-4-ICG-mediated PTT provided advanced TNBC tumor destruction efficiency with low systematic toxicity. Conclusion mAbNectin-4-based radioimmunoimaging provides visualization tools for the stratification and diagnosis for TNBC, and the corresponding mAbNectin-4-mediated PTT shows a powerful anti-tumor effect. Our findings demonstrate that this Nectin-4 targeting strategy offers a simple theranostic platform for TNBC.

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Section: Methodsmentioning

confidence: 99%

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer

et al. 2022

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“…IgG-[L]-scFv structure was adopted to produce TF-TCB in this study to avert the chain mis-pairing problems in bispecific antibody production 34 , 56 . Our results demonstrate that the TF-TCB could be expressed and purified similar as a normal IgG1, providing the potential for large-scale production with good manufacturing practice.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a novel bispecific antibody targeting tissue factor-positive tumors with T cell engagement

Pan

Chen

Xiao

et al. 2022

Acta Pharmaceutica Sinica B

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“…We considered it might be because the extra CD3 fragment blocked the CD3 antigen on human PBMC in the system or T cell exhaustion on the early stage of administration ( Wherry and Kurachi, 2015 ). The NOD/SCID mouse was widely used in the pre-clinical stage of immunotherapy ( Amann et al, 2009 ; Chen et al, 2021 ; Sun et al, 2021 ). However, human immune cells with a limited half-life in the treatment cycle might hard to infiltrate into tumor tissues ( Shultz et al, 2005 ).…”

Section: Discussionmentioning

confidence: 99%

IgG-like Bispecific Antibody CD3×EpCAM Generated by Split Intein Against Colorectal Cancer

et al. 2022

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Background: Colorectal cancer is a commonly diagnosed cancer with high mortality worldwide. Postoperative recidivation and metastasis still are the main challenges in clinical treatments. Thus, it is urgent to develop new therapies against colorectal cancer. Epithelial Cell Adhesion Molecule (EpCAM) is overexpressed in colorectal cancer cells and strongly associated with cancer development. Bispecific antibody (BsAb) is a kind of promising immunotherapy, which could recognize T cells and cancer cells simultaneously to achieve the anti-tumor effects.Methods: A bispecific antibody targeting EpCAM and CD3 with IgG format was genereated by split intein based on the Bispecific Antibody by Protein Splicing” platform. In vitro, the affinity of CD3×EpCAM BsAb was determined by Biolayer interferometry, its cytotoxicity was detected by LDH release assay, T cell recruitment and activation was detected by Flow Cytometry. In vivo, its pharmacokinetic parameters were detected, and anti-tumor effects were evaluated on the tumor cell xenograft mouse model.Results: The results showed that the CD3×EpCAM BsAb could activate and recruit T cells via binding colorectal cells and T cells, which could lead to more potent cytotoxicity to various colorectal cell lines than its parent EpCAM monoclonal antibody (mAb) in vitro. The CD3×EpCAM BsAb had similar pharmacokinetic parameters with EpCAM mAb and inhibits tumor growth on the SW480 tumor cell xenograft mouse model.Conclusion: The CD3×EpCAM BsAb could be a promising candidate for colorectal cancer treatment.

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A Novel Bispecific Antibody Targeting CD3 and Lewis Y with Potent Therapeutic Efficacy against Gastric Cancer

Cited by 18 publications

References 49 publications

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer

Characterization of a novel bispecific antibody targeting tissue factor-positive tumors with T cell engagement

IgG-like Bispecific Antibody CD3×EpCAM Generated by Split Intein Against Colorectal Cancer

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