Combinatorial approach to increase efficacy of Cetuximab, Panitumumab and Trastuzumab by dianthin conjugation and co-application of SO1861

Gilabert-Oriol, Roger; Weng, Alexander; Trautner, Alexandra; Weise, Christoph; Schmid, Daniel T.; Bhargava, Cheenu; Niesler, Nicole; Wookey, Peter J.; Fuchs, Hendrik; Thakur, Mayank

doi:10.1016/j.bcp.2015.07.040

Cited by 22 publications

(33 citation statements)

References 38 publications

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“…Enhancement factors of more than one million were observed (Weng et al ., ). The IC 50 for the above‐mentioned antibody– His Dianthin conjugates in the presence of SO1861 was 1.5, 23, and 5.3 p m , respectively (Gilabert‐Oriol et al ., ). Real‐time cytotoxicity studies also revealed the combination treatment to be more superior compared to monotherapy with only targeted toxin.…”

Section: Discussionmentioning

confidence: 97%

“…EGFR-targeting toxins in synergism to the endosomal escape mechanism of SO1861 might have an important regulatory role in the control of tumor growth in xenografts bearing human adenocarcinoma pancreatic tumors. A strong evidence for this hypothesis is based on in vitro (Bachran et al, 2011;Gilabert-Oriol et al, 2015;Weng et al, 2012) as well as in vivo studies that were previously performed in BALB/c and nude mice demonstrating very strong synergistic effects of the combination therapy for mammary and colon carcinoma (Bachran et al, 2009;Gilabert-Oriol et al, 2013c;von Mallinckrodt et al, 2014). The aim of our study was to investigate whether the combinatory treatment with SO1861 is also suitable to treat pancreatic adenocarcinoma, which is characterized by aggressive growth and a very low overall five-year survival rate of less than 4% (Kleeff et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the difference in the cytotoxic effect between single and combination therapy proved to be more eminent in BxPC-3 cells, as portrayed by an IC 50 of 100 nM in monotherapy and 0.17 nM in combination therapy within 48 h. Studies on saporin-based targeted toxins showed that the IC 50 is strongly dependent on target receptor expression and can range from 2.5 nM to 206 nM in the absence of endosomal escape enhancers (Bachran et al, 2010b). For His Dianthin-EGF, the IC 50 was only 0.45 nM on transfected cells that highly overexpress EGFR (Weng et al, 2012) and greater than 10 nM for His Dianthin chemically conjugated to panitumumab, trastuzumab, or cetuximab (Gilabert-Oriol et al, 2015). The effect by endosomal escape enhancers depends on the cell line, the targeting moiety, target receptor expression, and the structure of the enhancer.…”

Section: Discussionmentioning

confidence: 99%

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Targeted dianthin is a powerful toxin to treat pancreatic carcinoma when applied in combination with the glycosylated triterpene SO1861

et al. 2017

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Targeted cancer therapy provides the basis for the arrest of tumor growth in aggressive pancreatic carcinoma; however, a number of protein‐based targeted toxins lack efficacy due to insufficient endosomal escape after being endocytosed. Therefore, we tested a fusion protein of the ribosome‐inactivating protein dianthin and human epidermal growth factor in combination with a glycosylated triterpene (SO1861) that serves as an endosomal escape enhancer. In vitro investigations with the pancreatic carcinoma cell lines BxPC‐3 and MIA PaCa‐2 revealed no significant differences to off‐target cells in the half maximal inhibitory concentration (IC 50) for the fusion protein. In contrast, combination with SO1861 decreased the IC 50 for BxPC‐3 cells from 100 to 0.17 nm, whereas control cells remained unaffected. Monotherapy of BxPC‐3 xenografts in CD‐1 nude mice led to a 51.7% average reduction in tumor size (40.8 mm3) when compared to placebo; however, combined treatment with SO1861 resulted in a more than 13‐fold better efficacy (3.0 mm3 average tumor size) with complete regression in 80% of cases. Immunohistochemical analyses showed that tumor cells with lower target receptor expression are, in contrast to the combination therapy, able to escape from the monotherapy, which finally results in tumor growth. At the effective concentration, we did not observe liver toxicity and saw no other side effects with the exception of a reversible skin hardening at the SO1861 injection site, alongside an increase in platelet counts, plateletcrit, and platelet distribution width. In conclusion, combining a targeted toxin with SO1861 is proven to be a very promising approach for pancreatic cancer treatment.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Targeted dianthin is a powerful toxin to treat pancreatic carcinoma when applied in combination with the glycosylated triterpene SO1861

et al. 2017

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“…Similarly, a competitive fluorescence-based real-time binding assay of dianthin-cetuximab also exhibits high receptor specificity. After blocking of EGF receptors by unconjugated antibodies, the immunotoxin was not able to bind [133]. The application of saponins does not affect the binding specificity of these immunotoxins.…”

Section: Endosomal Escape In Cell Culture Modelsmentioning

confidence: 99%

“…While independent of the targeting moiety of the targeted toxin, the saponin-mediated enhancement factor of the cytotoxic effect is dependent on the cell line and on the expression and internalization level of the target molecule (Table 1) [33,38,40,41,44,110,133]. The enhancement factor is defined as the ratio of the concentrations in the absence and presence of saponins required for half maximal growth inhibition compared to untreated controls.…”

Section: Endosomal Escape In Cell Culture Modelsmentioning

confidence: 99%

Glycosylated Triterpenoids as Endosomal Escape Enhancers in Targeted Tumor Therapies

et al. 2017

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Protein-based targeted toxins play an increasingly important role in targeted tumor therapies. In spite of their high intrinsic toxicity, their efficacy in animal models is low. A major reason for this is the limited entry of the toxin into the cytosol of the target cell, which is required to mediate the fatal effect. Target receptor bound and internalized toxins are mostly either recycled back to the cell surface or lysosomally degraded. This might explain why no antibody-targeted protein toxin has been approved for tumor therapeutic applications by the authorities to date although more than 500 targeted toxins have been developed within the last decades. To overcome the problem of insufficient endosomal escape, a number of strategies that make use of diverse chemicals, cell-penetrating or fusogenic peptides, and light-induced techniques were designed to weaken the membrane integrity of endosomes. This review focuses on glycosylated triterpenoids as endosomal escape enhancers and throws light on their structure, the mechanism of action, and on their efficacy in cell culture and animal models. Obstacles, challenges, opportunities, and future prospects are discussed.

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Dianthin-30 or gelonin versus monomethyl auristatin E, each configured with an anti-calcitonin receptor antibody, are differentially potent in vitro in high-grade glioma cell lines derived from glioblastoma

Gilabert-Oriol

Furness

Stringer

et al. 2017

Cancer Immunol Immunother

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We have reported that calcitonin receptor (CTR) is widely expressed in biopsies from the lethal brain tumour glioblastoma by malignant glioma and brain tumour-initiating cells (glioma stem cells) using anti-human CTR antibodies. A monoclonal antibody against an epitope within the extracellular domain of CTR was raised (mAb2C4) and chemically conjugated to either plant ribosome-inactivating proteins (RIPs) dianthin-30 or gelonin, or the drug monomethyl auristatin E (MMAE), and purified. In the high-grade glioma cell line (HGG, representing glioma stem cells) SB2b, in the presence of the triterpene glycoside SO1861, the EC for mAb2C4:dianthin was 10.0 pM and for mAb2C4:MMAE [antibody drug conjugate (ADC)] 2.5 nM, 250-fold less potent. With the cell line U87MG, in the presence of SO1861, the EC for mAb2C4:dianthin was 20 pM, mAb2C4:gelonin, 20 pM, compared to the ADC (6.3 nM), which is >300 less potent. Several other HGG cell lines that express CTR were tested and the efficacies of mAb2C4:RIP (dianthin or gelonin) were similar. Co-administration of the enhancer SO1861 purified from plants enhances lysosomal escape. Enhancement with SO1861 increased potency of the immunotoxin (>3 log values) compared to the ADC (1 log). The uptake of antibody was demonstrated with the fluorescent conjugate mAb2C4:Alexa Fluor 568, and the release of dianthin-30:Alexa Fluor488 into the cytosol following addition of SO1861 supports our model. These data demonstrate that the immunotoxins are highly potent and that CTR is an effective target expressed by a large proportion of HGG cell lines representative of glioma stem cells and isolated from individual patients.

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Combinatorial approach to increase efficacy of Cetuximab, Panitumumab and Trastuzumab by dianthin conjugation and co-application of SO1861

Cited by 22 publications

References 38 publications

Targeted dianthin is a powerful toxin to treat pancreatic carcinoma when applied in combination with the glycosylated triterpene SO1861

Targeted dianthin is a powerful toxin to treat pancreatic carcinoma when applied in combination with the glycosylated triterpene SO1861

Glycosylated Triterpenoids as Endosomal Escape Enhancers in Targeted Tumor Therapies

Dianthin-30 or gelonin versus monomethyl auristatin E, each configured with an anti-calcitonin receptor antibody, are differentially potent in vitro in high-grade glioma cell lines derived from glioblastoma

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