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

Giansanti, Francesco; Sabatini, D. M.; Pennacchio, Maria Rosaria; Scotti, S.; Angelucci, Francesco; Dhez, Anne-Chloé; Antonosante, Andrea; Cimini, Annamaria; Giordano, Antonio; Ippoliti, Rodolfo

doi:10.1002/jcb.25080

Cited by 8 publications

(8 citation statements)

References 42 publications

(47 reference statements)

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“…The recombinant fusion toxins with either one (h(CASK)-Saporin) or two (h(CASK) 2 -Saporin) PDZ domains were tested against several glioblastoma cell lines. Saponin SA1641 was able to increase the toxicity of Saporin and h(CASK) 2 -Saporin chimera in U87 Glioblastoma cell line (IC 50 < 10 −11 M and << 10 −12 M respectively), and allowed hCASK-Saporin to reach an IC 50 of 10 −10 M [ 99 , 100 ].…”

Section: Understanding the Intracellular Fate To Improve The Efficmentioning

confidence: 99%

Strategies to Improve the Clinical Utility of Saporin-Based Targeted Toxins

Giansanti

Flavell

Angelucci

et al. 2018

Toxins

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Plant Ribosome-inactivating proteins (RIPs) including the type I RIP Saporin have been used for the construction of Immunotoxins (ITxs) obtained via chemical conjugation of the toxic domain to whole antibodies or by generating genetic fusions to antibody fragments/targeting domains able to direct the chimeric toxin against a desired sub-population of cancer cells. The high enzymatic activity, stability and resistance to conjugation procedures and especially the possibility to express recombinant fusions in yeast, make Saporin a well-suited tool for anti-cancer therapy approaches. Previous clinical work on RIPs-based Immunotoxins (including Saporin) has shown that several critical issues must be taken into deeper consideration to fully exploit their therapeutic potential. This review focuses on possible combinatorial strategies (chemical and genetic) to augment Saporin-targeted toxin efficacy. Combinatorial approaches may facilitate RIP escape into the cytosolic compartment (where target ribosomes are), while genetic manipulations may minimize potential adverse effects such as vascular-leak syndrome or may identify T/B cell epitopes in order to decrease the immunogenicity following similar strategies as those used in the case of bacterial toxins such as Pseudomonas Exotoxin A or as for Type I RIP Bouganin. This review will further focus on strategies to improve recombinant production of Saporin-based chimeric toxins.

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Section: Understanding the Intracellular Fate To Improve The Efficmentioning

confidence: 99%

Strategies to Improve the Clinical Utility of Saporin-Based Targeted Toxins

Giansanti

Flavell

Angelucci

et al. 2018

Toxins

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“…The most used ligands as carriers can be proteins or peptides. Another strategy is to use peptide-drug-conjugates that are made up of small, synthetic peptides [ 103 , 104 , 105 , 106 , 107 , 108 ]. These molecules appear to have an even faster penetration and elimination than the small antibody fragments we have described [ 102 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

Antibody-Drug Conjugates: The New Frontier of Chemotherapy

Ponziani

Vittorio²,

Pitari

et al. 2020

IJMS

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In recent years, antibody-drug conjugates (ADCs) have become promising antitumor agents to be used as one of the tools in personalized cancer medicine. ADCs are comprised of a drug with cytotoxic activity cross-linked to a monoclonal antibody, targeting antigens expressed at higher levels on tumor cells than on normal cells. By providing a selective targeting mechanism for cytotoxic drugs, ADCs improve the therapeutic index in clinical practice. In this review, the chemistry of ADC linker conjugation together with strategies adopted to improve antibody tolerability (by reducing antigenicity) are examined, with particular attention to ADCs approved by the regulatory agencies (the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) for treating cancer patients. Recent developments in engineering Immunoglobulin (Ig) genes and antibody humanization have greatly reduced some of the problems of the first generation of ADCs, beset by problems, such as random coupling of the payload and immunogenicity of the antibody. ADC development and clinical use is a fast, evolving area, and will likely prove an important modality for the treatment of cancer in the near future.

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“…This latter property makes EV20 a good candidate for the generation of Antibody-Drug Conjugates (ADCs). Here, we describe EV20-Sap, a novel ADC obtained by coupling EV20 to the ribosome inactivating protein Saporin via chemical crosslinking [ 15 , 16 ]. In HER-3 expressing cancer cell lines, EV20-Sap demonstrated a powerful, specific and target-dependent killing activity.…”

Section: Introductionmentioning

confidence: 99%

EV20-Sap, a novel anti-HER-3 antibody-drug conjugate, displays promising antitumor activity in melanoma

et al. 2017

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Melanoma is the most biologically aggressive skin cancer of well established constitutive and induced resistance to pharmacological treatment. Despite the recent progresses in immunotherapies, many advanced metastatic melanoma patients still face a significant mortality risk. The aggressive nature of this disease sustains an urgent need for more successful, effective drugs. HER-3 - one of the four member of the tyrosin kinase epidermal growth factor receptors (EGFRs) family- is frequently overexpressed in solid tumors, including melanoma. Moreover, up-regulation of HER-3 and its ligand NRGβ-1 are associated with poor prognosis, thus suggesting this receptor as a suitable target for cancer therapy. Several monoclonal antibodies targeting HER-3 are currently available, but preliminary results from clinical testing of these agents reveal a modest efficacy. Thus, a substantial improvement over this immunotherapeutic approach could be offered by an anti-HER-3 based Antibody-Drug Conjugate (ADC). In the present paper, we describe the generation of an ADC obtained by coupling the HER-3 targeting antibody EV20 linked to the plant toxin Saporin (Sap). In vitro, this ADC displays a powerful, specific and target-dependent cytotoxic activity which correlates with the degree of expression and internalization of HER-3 on tumor cells. Furthermore, in a murine melanoma model, EV20-Sap treatment leads to a significant reduction of the number of pulmonary metastasis.

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

Cited by 8 publications

References 42 publications

Strategies to Improve the Clinical Utility of Saporin-Based Targeted Toxins

Strategies to Improve the Clinical Utility of Saporin-Based Targeted Toxins

Antibody-Drug Conjugates: The New Frontier of Chemotherapy

EV20-Sap, a novel anti-HER-3 antibody-drug conjugate, displays promising antitumor activity in melanoma

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