Ephrin receptor A10 is a promising drug target potentially useful for breast cancers including triple negative breast cancers

Nagano, Kazuya; Maeda, Yuka; Kanasaki, S.; Watanabe, Tomomichi; Yamashita, Takuya; Inoue, Masakí; Higashisaka, Kazuma; Yoshioka, Yasuo; Abe, Yasuhiro; Mukai, Yohei; Kamada, Haruhiko; Tsutsumi, Yasuo; Tsunoda, Shin-ichi

doi:10.1016/j.jconrel.2014.06.010

Cited by 42 publications

(47 citation statements)

References 40 publications

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“…To evaluate the utility of EphA10 as a drug target, we developed an anti-EphA10 mAb and administered it or a control mAb once a week in an intravenously xenografted mouse model. Tumor growth was significantly lower in the anti-EphA10 mAb–treated group than in the controls; this effect was dose dependent 38) (Fig. 2).…”

Section: Establishment Of Antibody Proteomics Technology: a High-thromentioning

confidence: 84%

“…We therefore analyzed the EphA10 production profile by using tissue microarrays and showed that EphA10 was produced in various subtypes of breast cancer — luminal A (54%), luminal B (68%), human epidermal growth factor receptor 2 (Her2)-enriched (64%), and triple negative breast cancer (TNBC) (67%) — but not in 35 kinds of normal tissue, except for the testis. 38) The TNBC subtype, which lacks the production of estrogen receptor, progesterone receptor, and Her2, is refractory to current treatments because of an absence of molecularly targeted drugs. Therefore, there is considerable interest worldwide in developing therapeutics against TNBC.…”

Section: Establishment Of Antibody Proteomics Technology: a High-thromentioning

confidence: 99%

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Development of novel drug delivery systems using phage display technology for clinical application of protein drugs

Nagano

Tsutsumi

2016

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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Attempts are being made to develop therapeutic proteins for cancer, hepatitis, and autoimmune conditions, but their clinical applications are limited, except in the cases of drugs based on erythropoietin, granulocyte colony–stimulating factor, interferon-alpha, and antibodies, owing to problems with fundamental technologies for protein drug discovery. It is difficult to identify proteins useful as therapeutic seeds or targets. Another problem in using bioactive proteins is pleiotropic actions through receptors, making it hard to elicit desired effects without side effects. Additionally, bioactive proteins have poor therapeutic effects owing to degradation by proteases and rapid excretion from the circulatory system. Therefore, it is essential to establish a series of novel drug delivery systems (DDS) to overcome these problems. Here, we review original technologies in DDS. First, we introduce antibody proteomics technology for effective selection of proteins useful as therapeutic seeds or targets and identification of various kinds of proteins, such as cancer-specific proteins, cancer metastasis–related proteins, and a cisplatin resistance–related protein. Especially Ephrin receptor A10 is expressed in breast tumor tissues but not in normal tissues and is a promising drug target potentially useful for breast cancer treatment. Moreover, we have developed a system for rapidly creating functional mutant proteins to optimize the seeds for therapeutic applications and used this system to generate various kinds of functional cytokine muteins. Among them, R1antTNF is a TNFR1-selective antagonistic mutant of TNF and is the first mutein converted from agonist to antagonist. We also review a novel polymer-conjugation system to improve the in vivo stability of bioactive proteins. Site-specific PEGylated R1antTNF is uniform at the molecular level, and its bioactivity is similar to that of unmodified R1antTNF. In the future, we hope that many innovative protein drugs will be developed by combining these technologies.

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Section: Establishment Of Antibody Proteomics Technology: a High-thromentioning

confidence: 84%

Section: Establishment Of Antibody Proteomics Technology: a High-thromentioning

confidence: 99%

Development of novel drug delivery systems using phage display technology for clinical application of protein drugs

Nagano

Tsutsumi

2016

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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“…To validate the usefulness of the antibody proteomics technology, we used the technology to identify several novel biomarkers and drug targets in three different disease states. Here, we introduce two potential biomarkers related to metastasis in lung cancer, 10,11) one potential biomarker related to cisplatin resistance in malignant mesothelioma, 12) and one potential therapeutic target in breast cancer, including refractory breast cancer [13][14][15] that were discovered by using the antibody proteomics technology.…”

Section: Discovery Of Novel Biomarkers and Drug Targets Through Validmentioning

confidence: 99%

Development and Evaluation of Antibody Proteomics Technology for Rapid and Comprehensive Identification of Potential Biomarkers and Therapeutic Targets

Nagano

2018

Biological & Pharmaceutical Bulletin

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Proteomics-based analyses are powerful means of identifying potentially useful proteins in the initial stage of drug development. Technological developments in the field of proteomics, and increases in the sensitivity of MS analyses, now facilitate identification and examination of increasingly small amounts of proteins that are differentially expressed in diseased versus normal tissues and can be candidate biomarkers or therapeutic targets. However, the current approach is for candidate proteins to be prioritized by research interest and then validated one by one; this is very inefficient. To address this issue, we have developed what we refer to as "antibody proteomics technology," which uses a phage antibody library and tissue microarray analysis to rapidly and comprehensively isolate monoclonal antibodies against candidate proteins for the identification of potential biomarkers and therapeutic targets. In our validation of this technology, we successfully identified oxysterol binding protein-like 5 and calumenin as potential biomarkers related to metastasis in lung cancer, annexin A4 as a potential biomarker related to cisplatin resistance in malignant mesothelioma, and Eph receptor A10 as a potential therapeutic target in breast cancer, including refractory breast cancer. These findings suggest that antibody proteomics technology has the potential to become a fundamental technology in drug discovery for the development of novel biomarkers and therapeutic targets.

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“…51 Anti-EphA10 is expressed in all subsets of breast cancer but is not expressed in normal breast tissue. 52 Nagano et al 53 revealed that the administration of an anti-EphA10 antibody significantly suppressed tumor growth in a xenograft mouse model, indicating anti-EphA10 as the target for breast cancer. To improve the targeting ability of loaded siRNA, cationic liposomes can be modified with To further investigate the targeting ability of EPSLR, competitive inhibition of free Eph was performed.…”

Section: In Vitro Cellular Uptake Of Epslrmentioning

confidence: 99%

“…It has been reported that anti-EphA10 was specifically expressed in various subtypes of breast cancer tissues, but not within most normal tissues, indicating that anti-EphA10 is a promising drug target potentially useful for breast cancers. 53 Therefore, the cytotoxicity of EPSLR is probably attributed to the fact that anti-EphA10 antibody decoration can facilitate EPSLR internalization into carcinoma cells. Furthermore, anti-EphA10 promoted cell proliferation following ligand stimulation.…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

Anti-EphA10 antibody-conjugated pH-sensitive liposomes for specific intracellular delivery of siRNA

Zang¹,

Ding²,

Zhao³

et al. 2016

IJN

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Therapeutic delivery of small interfering RNA (siRNA) is a major challenge that limits its potential clinical application. Here, a pH-sensitive cholesterol–Schiff base–polyethylene glycol (Chol–SIB–PEG)-modified cationic liposome–siRNA complex, conjugated with the recombinant humanized anti-EphA10 antibody (Eph), was developed as an efficient nonviral siRNA delivery system. Chol–SIB–PEG was successfully synthesized and confirmed with FTIR and 1 H-NMR. An Eph–PEG–SIB–Chol-modified liposome–siRNA complex (EPSLR) was prepared and characterized by size, zeta potential, gel retardation, and encapsulation efficiency. Electrophoresis results showed that EPSLR was resistant to heparin replacement and protected siRNA from fetal bovine serum digestion. EPSLR exhibited only minor cytotoxicity in MCF-7/ADR cells. The results of flow cytometry and confocal laser scanning microscopy suggested that EPSLR enhanced siRNA transfection in MCF-7/ADR cells. Intracellular distribution experiment revealed that EPSLR could escape from the endo-lysosomal organelle and release siRNA into cytoplasm at 4 hours posttransfection. Western blot experiment demonstrated that EPSLR was able to significantly reduce the levels of MDR1 protein in MCF-7/ADR cells. The in vivo study of DIR-labeled complexes in mice bearing MCF-7/ADR tumor indicated that EPSLR could reach the tumor site rather than other organs more effectively. All these results demonstrate that EPSLR has much potential for effective siRNA delivery and may facilitate its therapeutic application.

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Ephrin receptor A10 is a promising drug target potentially useful for breast cancers including triple negative breast cancers

Cited by 42 publications

References 40 publications

Development of novel drug delivery systems using phage display technology for clinical application of protein drugs

Development of novel drug delivery systems using phage display technology for clinical application of protein drugs

Development and Evaluation of Antibody Proteomics Technology for Rapid and Comprehensive Identification of Potential Biomarkers and Therapeutic Targets

Anti-EphA10 antibody-conjugated pH-sensitive liposomes for specific intracellular delivery of siRNA

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