Effect of the anti-receptor ligand-blocking 225 monoclonal antibody on EGF receptor endocytosis and sorting

Jaramillo, María; Leon, Zully; Grothé, Suzanne; Paul-Roc, Béatrice; Abulrob, Abedelnasser; McCourt., Maureen O’Connor

doi:10.1016/j.yexcr.2006.05.008

Cited by 87 publications

(79 citation statements)

References 56 publications

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“…S4). It was also not previously known whether any antibody-internalized receptor was trafficked to the lysosome (21,23). Here, we demonstrate that a distinct amount of cetuximab induced internalized EGFR is trafficked to the lysosomes.…”

Section: Resultsmentioning

confidence: 53%

“…This increased number of puncta formation suggests enhanced clustering of EGFR induced by nanoconjugation and suggests faster endocytosis by nanoconjugated C225. Furthermore, we demonstrated previously that preincubation of various cancer cells with It is also important to note here that the information regarding endocytic sorting of antibody-receptor complex and the mechanism of endocytosis is still lacking (21,23). We are demonstrating in this paper the mechanism and endocytic sorting of antibody-receptor complex in nanoconjugated and nonconjugated form.…”

Section: Resultsmentioning

confidence: 61%

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Nanoconjugation modulates the trafficking and mechanism of antibody induced receptor endocytosis

Bhattacharyya¹,

Bhattacharya²,

Curley

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

124

123

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Treatment with monoclonal antibody (mAbs) is a viable therapeutic option in cancer. Recently, these mAbs such as cetuximab, herceptin, etc., have been used as targeting agents to selectively deliver chemotherapeutics to cancerous cells. However, mechanisms of nanoparticles-mAbs interactions with the target cells and its effect on intracellular trafficking and mechanism are currently unknown. In this paper, we demonstrate that the distinct patterning and dynamics of anti-EGFR (epidermal growth factor receptor) antibody cetuximab (C225)-induced EGFR internalization in pancreatic cancer cells with variable receptor expression is altered upon nanoconjugation. Nanoconjugation uniformly enhanced C225-induced EGFR endocytosis in PANC-1, AsPC-1, and MiaPaca-2 cells, influenced its compartmentalization and regulated the involvement of dynamin-2 in the endocytic processes. Receptor endocytosis and its intracellular trafficking were monitored by confocal microscopy and transmission electron microscopy. The role of dynamin-2 in EGFR endocytosis was determined after overexpressing either wild-type dynamin-2 or mutant dynamin-2 in pancreatic cancer cells followed by tracking the receptor-antibody complex internalization by confocal microscopy. Significantly, these findings demonstrate that the nanoconjugation cannot be construed as an innocuous reaction involved in attaching the targeting agent to the nanoparticle, instead it may distinctly alter the cellular processes at the molecular level, at least antibody induced receptor endocytosis. This information is critical for successful design of a nanoparticle-based targeted drug delivery system for future clinical translation.EGFR | nanoparticle | dynamin | pancreatic cancer N anotechnology provides opportunities for biomedical applications that may improve human health care in the future (1-13). Engineered nanoparticles are evolving as promising candidates for various biological applications due to their tunable biophysical and biochemical properties (14-16). However, fundamental studies to understand the mechanism of cell-nanomaterial interactions are still lacking. To advance the successful development of biomedical nanotechnology for clinical use, vivid understanding of such mechanisms is essential.Epidermal growth factor receptor (EGFR) represents a unique target as over expression of EGFR has been implicated in the pathogenesis of many cancers (17, 18). Cetuximab (C225), a monoclonal anti-EGFR antibody, has been approved by the FDA for treatment of colon and head and neck cancers (19). Cetuximab is also in different phases of clinical trials for other cancers (20,21). However, the mechanism and pattern of C225 induced endocytosis of EGFR in pancreatic cancer cells of variable EGFR expression is not fully understood (20,21). Furthermore, the effect of nanoconjugation on the mechanism of C225 induced endocytosis remains to be investigated. Here, we demonstrate the mechanism and endocytic pattern of C225 and gold conjugated-C225 induced internalization of EGFR in pancreatic ...

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Section: Resultsmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 61%

Nanoconjugation modulates the trafficking and mechanism of antibody induced receptor endocytosis

Bhattacharyya¹,

Bhattacharya²,

Curley

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

124

123

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show abstract

“…It can therefore be estimated that EGF-saporin is approximately 25 times more effective in combination with PCI than cetuximab-saporin. EGF stimulates to a more rapid endocytosis of EGFR than cetuximab (Friedman et al 2005, Jaramillo et al 2006. The increased cytotoxicity after PCI of EGF-saporin compared to cetuximab-saporin could therefore be explained by a more effective endocytosis of the former, accumulating more toxin in the endo/lysosomal vesicles at the time of light exposure.…”

Section: Egf Versus Cetuximab As a Targeting Ligandmentioning

confidence: 97%

Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin

Weyergang

Selbo

Berg

2006

Journal of Controlled Release

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“…However, despite their high affinity for the target (21), higher concentrations are needed to affect the short-term cell viability in XTT assays. Cetuximab has an avidity of 1 nM on A431 cells (47), but its bivalent nature has been shown to induce receptor internalization (47,59), and antibody-induced EGFR dimerization is necessary for down-regulation of EGFR. This antibody-induced dimerization does not lead to receptor activation.…”

Section: Volume 286 • Number 48 • December 2 2011mentioning

confidence: 99%

Bispecific Designed Ankyrin Repeat Proteins (DARPins) Targeting Epidermal Growth Factor Receptor Inhibit A431 Cell Proliferation and Receptor Recycling

Boersma

Chao

Steiner

et al. 2011

Journal of Biological Chemistry

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Background:The EGF receptor (EGFR) is an important therapeutic target. Results: Bispecific anti-EGFR designed ankyrin repeat proteins (DARPins), alternative targeting molecules efficiently produced in bacteria, were shown to inhibit A431 cell proliferation and receptor recycling. Conclusion: One bispecific construct containing four DARPins showed a biological activity superior to that of the registered antibody cetuximab. Significance: Bispecific DARPins may form building blocks for tomorrow's cancer therapeutics.

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Effect of the anti-receptor ligand-blocking 225 monoclonal antibody on EGF receptor endocytosis and sorting

Cited by 87 publications

References 56 publications

Nanoconjugation modulates the trafficking and mechanism of antibody induced receptor endocytosis

Nanoconjugation modulates the trafficking and mechanism of antibody induced receptor endocytosis

Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin

Bispecific Designed Ankyrin Repeat Proteins (DARPins) Targeting Epidermal Growth Factor Receptor Inhibit A431 Cell Proliferation and Receptor Recycling

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