Novel EBV LMP1 C-terminal domain binding affibody molecules as potential agents for in vivo molecular imaging diagnosis of nasopharyngeal carcinoma

Kamara, Saidu; Guo, Yafei; Mao, Shanshan; Ye, Xiaoxian; Li, Qingfeng; Zheng, Ming‐Hua; Zhu, Jinshun; Zhang, Jing; Du, Wangqi; Zhu, Shanli; Zhang, Lifang

doi:10.1007/s00253-021-11559-6

Cited by 9 publications

(11 citation statements)

References 35 publications

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“…Some therapeutic affibodies have now entered preclinical and clinical trials for cancer treatment [ 5 ]. Recently, several affibodies using intracellular proteins as targets show great potential in cancer and other disease treatment [ 6 , 7 , 8 , 9 , 10 , 11 ]. We have previously developed the affibody Z HPV16E7 384 as a cervical cancer therapeutic agent [ 6 , 7 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several therapeutic affibodies have now entered preclinical and clinical trials for cancer treatment [ 5 ]. In more recent studies, several affibodies that target intracellular proteins show great potential in cancer and other disease therapy, which include the affibodies targeting HPV16 E6 or E7 for cervical cancer, those targeting the EBV LMP1 C-terminal domain or LMP2A N-terminal domain for nasopharyngeal carcinoma, and those targeting Chlamydia trachomatis MOMP for Chlamydia trachomatis [ 6 , 7 , 8 , 9 , 10 , 11 ]. However, a key question that remains to be answered is whether and how the affibodies enter the target cells to interact with intracellular target proteins, leading to the inhibition of the target cell proliferation and finally to destroy the target cells.…”

Section: Introductionmentioning

confidence: 99%

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The HPV16E7 Affibody as a Novel Potential Therapeutic Agent for Treating Cervical Cancer Is Likely Internalized through Dynamin and Caveolin-1 Dependent Endocytosis

et al. 2022

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Affibodies targeting intracellular proteins have a great potential to function as ideal therapeutic agents. However, little is known about how the affibodies enter target cells to interact with intracellular target proteins. We have previously developed the HPV16E7 affibody (ZHPV16E7384) for HPV16 positive cervical cancer treatment. Here, we explored the underlying mechanisms of ZHPV16E7384 and found that ZHPV16E7384 significantly inhibited the proliferation of target cells and induced a G1/S phase cell cycle arrest. Furthermore, ZHPV16E7384 treatment resulted in the upregulation of retinoblastoma protein (Rb) and downregulation of phosphorylated Rb (pRb), E2F1, cyclin D1, and CDK4 in the target cells. Moreover, treatment with dynamin or the caveolin-1 inhibitor not only significantly suppressed the internalization of ZHPV16E7384 into target cells but also reversed the regulation of cell cycle factors by ZHPV16E7384. Overall, these results indicate that ZHPV16E7384 was likely internalized specifically into target cells through dynamin- and caveolin-1 mediated endocytosis. ZHPV16E7384 induced the cell cycle arrest in the G1/S phase at least partially by interrupting HPV16E7 binding to and degrading Rb, subsequently leading to the downregulation of E2F1, cyclin D1, CDK4, and pRb, which ultimately inhibited target cell proliferation. These findings provide a rationale of using ZHPV16E7384 to conduct a clinical trial for target therapy in cervical cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The HPV16E7 Affibody as a Novel Potential Therapeutic Agent for Treating Cervical Cancer Is Likely Internalized through Dynamin and Caveolin-1 Dependent Endocytosis

et al. 2022

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“…A phage display of combinatorial library was constructed in our laboratory, from which three a body molecules that bind with high a nity and speci city to EBV LMP1-C were selected [32]. The Z LMP1-C a body molecules were selected for further study.…”

Section: Protein Expression and Puri Cationmentioning

confidence: 99%

“…Recently, over 400 studies have been reported in which a body molecules have been generated and used in a variety of applications [21]. The a body molecules targeted proteins include epidermal growth factor (EGFR) [22,23], human epidermal growth factor 2 (HER2) [24,25], human epidermal growth factor 3 (HER3) [26,27], vascular endothelial growth factor (VEGF) [28], human papilloma virus type 16 E7 (HPV16 E7) [29,30], LMP2A-N [31], and LMP1-C [32], offer a great potential in diagnosis and therapy.…”

Section: Introductionmentioning

confidence: 99%

“…In our previous study, we generated three novel LMP1-C terminal domain binding a body molecules (Z LMP1−C 15, Z LMP1−C 114 and Z LMP1−C 277) and their ability to bind to recombinant and native LMP1-C terminal protein were investigated both in vitro and in vivo [32]. In this study, we explored the antitumor effects of Z LMP1−C a body molecules on EBV-positive NPC cell lines, and further elucidate the inhibitory effects of Z LMP1−C 277 on MEK/ERK/p90RSK signaling pathway in NPC cells.…”

Section: Introductionmentioning

confidence: 99%

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EBV LMP1-C terminal binding affibody molecule downregulates MEK/ERK/p90RSK pathway and inhibits the proliferation of nasopharyngeal carcinoma cells in mouse tumor xenograft models

Guo

Kamara

Zhang

et al. 2022

Preprint

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Nasopharyngeal carcinoma (NPC), is an Epstein-Barr virus (EBV) associated malignancy most common in Southern China and Southeast Asia. In southern China, it is one of the major causes of cancer-related death. Despite improvement in radiotherapy and chemotherapy techniques, locoregional recurrence and distant metastasis remains the major causes for failure of treatment in NPC patients. Therefore, finding new specific drug targets for treatment interventions are urgently needed. Here, we report three potential ZLMP1−C affibody molecules (ZLMP1−C15, ZLMP1−C114 and ZLMP1−C277) that showed specific binding interactions for recombinant and native EBV LMP1 as determined by epitope mapping, co-localization and co-immunoprecipitation assays. The ZLMP1−C affibody molecules exhibited high antitumor effects on NPC-positive cell lines and displayed minimal cytotoxicity towards NPC-negative cell line. Moreover, ZLMP1−C277 showed higher antitumor efficacy than ZLMP1−C15 and ZLMP1−C114 affibody molecules. The ability of ZLMP1−C277 decrease the phosphorylation levels of up-stream activator phospho-Raf-1(Ser338), phospho-MEK1/2(Ser217/Ser221), phospho-ERK1/2(Thr202/Thr204), thereby leading to downstream suppression of phospho-p90RSK(Ser380) and transcription factor c-Fos. Importantly, tumor growth was reduced in tumor-bearing mice treated with ZLMP1−C277 and caused no apparent toxicity. Taken together, our findings provide evidence that ZLMP1−C277 as a promising therapeutic agent in EBV-associated NPC.

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Novel affibody molecules targeting the AXL extracellular structural domain for molecular imaging and targeted therapy of gastric cancer

Zhang,

Zheng,

Cai

et al. 2024

Gastric Cancer

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Gastric cancer (GC) has a poor prognosis and high mortality because it is often diagnosed at an advanced stage. Targeted therapeutics are considered an important class for advanced GC treatment. However, the fewer effective therapeutic targets and the poor coverage of the GC population limit the use of GC targeted therapies. Recent research suggests that the AXL receptor tyrosine kinase (AXL) plays an vital role in the survival and proliferation of GC cells, and blocking AXL pathway may be an effective strategy for targeted therapies. On the other hand, the affibody molecule, with its small size and faster penetration of tissue, has great potential in tumor imaging and targeted therapy. In this study, we report the novel AXL-binding affibody molecules (ZAXL:239) screened by a phage-displayed peptide library. The ZAXL:239 could specifically bind and interact with AXL proteins in vitro and in vivo, as demonstrated by surface plasmon resonance, co-immunoprecipitation, immuno-fluorescence co-localization, and near infrared fluorescent imaging. In addition, ZAXL:239 affibody molecules could significantly inhibit the proliferative activity and induce apoptosis of AXL-positive GC cells by decreasing the phosphorylation levels of the PI3K/AKT1 and MEK/ERK pathway, leading to the suppression of the downstream nuclear protein c-myc. Moreover, ZAXL:239 was found to have significant anti-tumor effects in AXL-positive GC transplantation tumor nude mouse models. In brief, we provide strong evidence that the novel ZAXL:239 affibody molecules have great potential as a potent tumor-specific molecular imaging and targeted therapeutic agents for GC.

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Novel EBV LMP1 C-terminal domain binding affibody molecules as potential agents for in vivo molecular imaging diagnosis of nasopharyngeal carcinoma

Cited by 9 publications

References 35 publications

The HPV16E7 Affibody as a Novel Potential Therapeutic Agent for Treating Cervical Cancer Is Likely Internalized through Dynamin and Caveolin-1 Dependent Endocytosis

The HPV16E7 Affibody as a Novel Potential Therapeutic Agent for Treating Cervical Cancer Is Likely Internalized through Dynamin and Caveolin-1 Dependent Endocytosis

EBV LMP1-C terminal binding affibody molecule downregulates MEK/ERK/p90RSK pathway and inhibits the proliferation of nasopharyngeal carcinoma cells in mouse tumor xenograft models

Novel affibody molecules targeting the AXL extracellular structural domain for molecular imaging and targeted therapy of gastric cancer

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