A CXCR4‐Targeted Site‐Specific Antibody–Drug Conjugate

Kularatne, Sumith A.; Deshmukh, V.; Ma, Jennifer; Tardif, Virginie; Lim, Reyna K. V.; Pugh, Holly; Sun, Ying; Manibusan, Anthony; Sellers, Aaron; Barnett, Richard S.; Srinagesh, Shailaja; Forsyth, Jane; Hassenpflug, Wolf; Tian, Feng; Javahishvili, Tsotne; Felding-Habermann, Brunhilde; Lawson, Brian R.; Kazane, Stephanie A.; Schultz, Peter G.

doi:10.1002/anie.201408103

Cited by 58 publications

(50 citation statements)

References 33 publications

(19 reference statements)

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“…Previous study revealed the enhanced CXCR4 expression was involved in distant metastasis of human osteosarcoma cells [36]. In addition, the CXCR4 blocking antibody eliminated pulmonary lesions from human osteosarcoma cells in a lung-seeding tumor model [37]. Consistently, the apoptotic protein expression levels including PARP, caspase-3, caspase-8, and caspase-9 were obviously enhanced after CXCR4 shRNA treatment, whereas Bid protein expression level was expectedly decreased with CXCR4 shRNA treatment in osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

Effect of CXCR4 on Apoptosis in Osteosarcoma Cells via the PI3K/Akt/NF-κβ Signaling Pathway

Jiang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Osteosarcoma, the most common primary bone malignancy, arises from primitive transformed cells of mesenchymal origin with the worldwide increasing morbidity and mortality. Previous studies found apoptosis of osteosarcoma cells was essential for an effective manner to improve the progress of osteosarcoma, and CXCR4 has been demonstrated to be relevant with various tumor progress and metastasis. Methods: The proliferation of cells transfected with CXCR4 shRNA and control shRNA were measured by BrdU assay. Apoptosis was detected by flow cytometry. Apoptotic protein expression levels were detected by Western blot. Caspase activity was detected by Colorimetric Assay Kits using microplate reader. Activation of NF-κβ signaling after CXCR4 down-regulation in osteosarcoma cells was examined by constructing NF-κβ promoter luciferase reporter plasmid. The expression and activation of NF-κβ Signaling relevant protein were analyzed to investigate the relationship between Akt and NF-κβ signaling after the down-regulation of CXCR4 in osteosarcoma cells. Results: Down-regulation of CXCR4 significantly reduced the cell proliferation, while remarkably increased the cell apoptosis and apoptotic protein expression levels in osteosarcoma cells. Furthermore, down-regulation of CXCR4 induced cell apoptosis was caspase dependent in osteosarcoma cells. This study also showed CXCR4 down-regulation induced apoptosis through inhibiting PI3K/Akt/NF-κβ signaling pathway. In addition, endoplasmic reticulum stress (ERS) activation was involved in cell apoptosis induced down-regulation of CXCR4. Knockdown of partial ERS relevant proteins followed down-regulation of CXCR4 significantly inhibited cell apoptosis and the apoptotic protein expression levels. Conclusions: Taken together, the results demonstrated that down-regulation of CXCR4 could induce apoptosis of human osteosarcoma cells through inhibiting PI3K/Akt/NF-κβ signaling pathway, indicating that CXCR4 could be vital for the clinical therapy of osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

Effect of CXCR4 on Apoptosis in Osteosarcoma Cells via the PI3K/Akt/NF-κβ Signaling Pathway

Jiang

et al. 2018

Cell Physiol Biochem

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“…Importantly, the site and stoichiometry of conjugation were found to affect the pharmacokinetics and efficacy of the ADC. Similarly, sitespecific ADCs have been generated that target CXCR4-positive metastatic cancer cells, and this technology is now being applied outside of oncology in the preparation of ADCs for the treatment of inflammatory, autoimmune, and metabolic disease (Kularatne et al 2014). Other constructs, including antibodies conjugated to imaging probes or two different drugs with synergistic effects, are being explored.…”

Section: The Design Of Proteins With Novel Properties Using Ncaasmentioning

confidence: 99%

At the Interface of Chemical and Biological Synthesis: An Expanded Genetic Code

Xiao

Schultz

2016

Cold Spring Harb Perspect Biol

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112

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The ability to site-specifically incorporate noncanonical amino acids (ncAAs) with novel structures into proteins in living cells affords a powerful tool to investigate and manipulate protein structure and function. More than 200 ncAAs with diverse biological, chemical, and physical properties have been genetically encoded in response to nonsense or frameshift codons in both prokaryotic and eukaryotic organisms with high fidelity and efficiency. In this review, recent advances in the technology and its application to problems in protein biochemistry, cellular biology, and medicine are highlighted.

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“…| 107 biologics. 55,56 Recently, the Schultz group demonstrated the incorporation of two orthogonal aminoacyl-tRNA synthetase and tRNA pairs in a mammalian cell line opening up the possibility of adding imaging and cytotoxins at different sites. 57 A similar approach has been implemented using cell-free synthetic approaches.…”

Section: Incorporation Of Non-natural Amino Acidsmentioning

confidence: 99%

Improving theranostics in pancreatic cancer

King

Bouvet

Singh

et al. 2017

Journal of Surgical Oncology

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Background Pancreatic cancer is the fourth most deadly cancer in the US, and is expected to be the second most deadly by 2030. The major difficulty in treating pancreatic cancer is the late onset of symptoms. Generally, patients show metastatic disease by the time of diagnosis, with a survival rate of 5% beyond 5 years. In patients without metastatic disease, surgical resection increases 5 year survival rate to 25%. The remaining 75% succumb to undetected metastases. Clearly, improvements to both detection, surgical intervention, and therapeutic strategies will be needed to improve patient outcome in pancreatic cancer. Methods Recent literature has been surveyed and atomic models of new therapeutic appoaches were generated. Results and Conclusions Here, we focus on the recent progress employing monoclonal antibodies (mAbs) to target pancreatic cancer associated markers, and more specifically on recent chemical and protein engineering efforts to improve the homogeneity, stability, and administration of mAbs to precisely delivery imaging agents and cytotoxins to sites of disease.

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A CXCR4‐Targeted Site‐Specific Antibody–Drug Conjugate

Cited by 58 publications

References 33 publications

Effect of CXCR4 on Apoptosis in Osteosarcoma Cells via the PI3K/Akt/NF-κβ Signaling Pathway

Effect of CXCR4 on Apoptosis in Osteosarcoma Cells via the PI3K/Akt/NF-κβ Signaling Pathway

At the Interface of Chemical and Biological Synthesis: An Expanded Genetic Code

Improving theranostics in pancreatic cancer

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