Saponins modulate the intracellular trafficking of protein toxins

Weng, Alexander; Thakur, Mayank; Mallinckrodt, Benedicta von; Beceren‐Braun, Figen; Gilabert-Oriol, Roger; Wiesner, Burkard; Eichhorst, Jenny; Böttger, Stefan; Melzig, Matthias F.; Fuchs, Hendrik

doi:10.1016/j.jconrel.2012.10.002

Cited by 59 publications

(90 citation statements)

References 30 publications

(33 reference statements)

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“…In fact, anti-CD103 mAb (M290) conjugated to saporin, a ribosomeinactivating protein [28], has been evaluated against CD103 + CD8 + cells in previous studies [9,29]. However, such a protein-conjugated antibody was reported to induce a host immune response directed against the heterogonous toxin, leading to shortened half-lives and neutralization of the cytotoxic potential of the immunotoxins [30,31]. In addition, the non-specific toxicities of M290-SAP, such as ascites and body weight loss, might be related to the larger molecular weight of saporin (approximately 30 kDa), which can cause such conjugates to be difficult to discharge from the kidney.…”

Section: Discussionmentioning

confidence: 99%

Efficient elimination of CD103-expressing cells by anti-CD103 antibody drug conjugates in immunocompetent mice

Mang

Zhao

Zeng

et al. 2015

International Immunopharmacology

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Section: Discussionmentioning

confidence: 99%

Efficient elimination of CD103-expressing cells by anti-CD103 antibody drug conjugates in immunocompetent mice

Mang

Zhao

Zeng

et al. 2015

International Immunopharmacology

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“…For leakage inducing systems, other solutions have been sought and found. For instance, a saponin was identified that specifically integrates into endosomes and thus retains the specificity of the targeted toxin, which only reaches the endosomes of tumor cells [103]. In case of physicochemical techniques, PCI itself has specificity for the tumor tissue.…”

Section: Discussionmentioning

confidence: 99%

“…The effect is based on a poorly understood interaction between a few particular saponin species out of many thousands and the plant Type-I-RIPs saporin and dianthin [102]. Surface plasmon resonance measurements point to a transient binding of saponins to the toxin components of targeted toxins in a pH-dependent manner [103]. These saponins when used at sub-lytic concentrations specifically mediate the release of saporin from an intracellular vesicular compartment into the cytosol without affecting the integrity of the plasma membrane.…”

Section: Leakage-inducing Moleculesmentioning

confidence: 99%

“…These saponins when used at sub-lytic concentrations specifically mediate the release of saporin from an intracellular vesicular compartment into the cytosol without affecting the integrity of the plasma membrane. The relevant intracellular compartments were identified as late endosomes and lysosomes [103]. Endosomal acidification is a prerequisite for the saponin-mediated release of saporin [103,104] and all saponins with endosomal escape enhancing properties exhibit a characteristic electrophoretic mobility [105].…”

Section: Leakage-inducing Moleculesmentioning

confidence: 99%

“…The relevant intracellular compartments were identified as late endosomes and lysosomes [103]. Endosomal acidification is a prerequisite for the saponin-mediated release of saporin [103,104] and all saponins with endosomal escape enhancing properties exhibit a characteristic electrophoretic mobility [105]. Targeted toxins in combination with saponins enter cells via clathrin-and actin-dependent pathways [104].…”

Section: Leakage-inducing Moleculesmentioning

confidence: 99%

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Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins

Fuchs

Bachran²,

Flavell

et al. 2013

Antibodies

Self Cite

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Membranes are vital barriers by which cells control the flux of molecules and energy between their exterior and interior and also between their various intracellular compartments. While numerous transport systems exist for ions and small molecules, the cytosolic uptake of larger biological molecules and in particular antibody-targeted drugs, is a big challenge. Inducing leakage of the plasma membrane is unfavorable since the target cell specificity mediated by the antibody would likely be lost in this case. After binding and internalization, the antibody drug conjugates reach the endosomes. Thus, enforcing the endosomal escape of anti-tumor toxins without affecting the integrity of other cellular membranes is of paramount importance. Different strategies have been developed in the last decades to overcome endosomal accumulation and subsequent lysosomal degradation of targeted protein-based drugs. In this review we summarize the various efforts made to establish efficient techniques to disrupt the endosomal membrane barrier including the use of molecular ferries such as cell penetrating peptides or viral membrane fusion proteins, endosomal leakage inducing molecules such as saponins or monensin and physicochemical methods as represented by photochemical internalization.

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PDZ Domain in the Engineering and Production of a Saporin Chimeric Toxin as a Tool for targeting Cancer Cells

Giansanti

Sabatini

Pennacchio

et al. 2015

J of Cellular Biochemistry

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In this paper we have studied a PDZ protein domain as a possible tool for cellular targeting of the ribosome inactivating protein Saporin, exploiting the ability of PDZ domains to recognize and bind short peptide sequences located at the C-terminus of a cognate protein. We have focused our attention on the PDZ domain from hCASK (Human calcium/calmodulin-dependent serine protein kinase) that binds extracellular CD98 in epithelial cells, being this antigen recognized as a marker for several human tumors and particularly considered a negative prognostic marker for human glioblastoma. We produced recombinant fusions of one or two hCASK-PDZ domains with the ribosome inactivating protein Saporin and assayed them on two human glioblastoma cell lines (GL15 and U87). These constructs proved to be toxic, with increasing activity as a function of the number of PDZ domains, and induce cell death by apoptotic mechanisms in a dose-dependent and/or time dependent manner.

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Saponins modulate the intracellular trafficking of protein toxins

Cited by 59 publications

References 30 publications

Efficient elimination of CD103-expressing cells by anti-CD103 antibody drug conjugates in immunocompetent mice

Efficient elimination of CD103-expressing cells by anti-CD103 antibody drug conjugates in immunocompetent mice

Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins

PDZ Domain in the Engineering and Production of a Saporin Chimeric Toxin as a Tool for targeting Cancer Cells

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