Targeted therapeutic RNases (ImmunoRNases)

Schirrmann, Thomas; Krauß, Jürgen; Arndt, Michaela A.E.; Rybak, Susanna M.; Dübel, Stefan

doi:10.1517/14712590802631862

Cited by 53 publications

(34 citation statements)

References 102 publications

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“…In addition to its potent cytotoxicity against diverse cancer cell lines in vitro, (Q)-hRS7 was shown to be effective in inhibiting the growth of Calu-3 human lung cancer xenografts in nude mice, thus validating the antitumor activity and stability of (Q)-hRS7 in vivo, as well as confirming the suitability of adding Trop-2 to the current list of antigens on solid cancers targeted by immunotoxins (31)(32)(33)37). In conclusion, we have shown that an amphibian RNase recombinantly fused with a humanized anti-Trop-2 antibody shows selective and potent cytotoxicity against a variety of epithelial cancers, both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 72%

“…Compared with immunotoxins made from toxins of plant or bacterial origin (31), for which clinical trials in cancer therapy have been completed or are ongoing for quite a few (32)(33)(34), the advancement of antibodytargeted RNases, called ImmunoRNases (35,36), is relatively moderate, with the majority developed for treating hematologic malignancies and the targeting components conferred by some forms of scFv (37). To date, ImmunoRNases have not been evaluated in patients with any cancer.…”

Section: Discussionmentioning

confidence: 99%

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Ranpirnase (Frog RNase) Targeted with a Humanized, Internalizing, Anti–Trop-2 Antibody Has Potent Cytotoxicity against Diverse Epithelial Cancer Cells

Chang

Gupta

Michel

et al. 2010

Molecular Cancer Therapeutics

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Ranpirnase (Rap), an amphibian RNase, has been extensively studied both preclinically and clinically as an antitumor agent. Rap can be administered repeatedly to patients without any untoward immune response, with reversible renal toxicity reported to be dose limiting. To enhance its potency and targeted tumor therapy, we describe the generation of a novel IgG-based immunotoxin, designated 2L-Rap(Q)-hRS7, comprising Rap (Q), a mutant Rap with the putative N-glycosylation site removed, and hRS7, an internalizing, humanized antibody against Trop-2, a cell surface glycoprotein overexpressed in variety of epithelial cancers. The immunotoxin was generated recombinantly by fusing Rap(Q) to each of the two hRS7 light (L) chains at the NH 2 terminus, produced in stably transfected myeloma cells, purified by Protein A, and evaluated by a panel of in vitro studies. The results, including size-exclusion high-performance liquid chromatography, SDS-PAGE, flow cytometry, RNase activity, internalization, cell viability, and colony formation, showed its purity, molecular integrity, comparable affinity to hRS7 for binding to several Trop-2-expressing cell lines of different cancer types, and potency to inhibit growth of these cell lines at nanomolar concentrations. In addition, 2L-Rap (Q)-hRS7 suppressed tumor growth in a prophylactic model of nude mice bearing Calu-3 human non-small cell lung cancer xenografts, with an increase in the median survival time from 55 to 96 days (P < 0.01). These results warrant further development of 2L-Rap(Q)-hRS7 as a potential therapeutic for various Trop-2-expressing cancers, such as cervical, breast, colon, pancreatic, ovarian, and prostate cancers. Mol Cancer Ther; 9(8); 2276-86. ©2010 AACR.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Ranpirnase (Frog RNase) Targeted with a Humanized, Internalizing, Anti–Trop-2 Antibody Has Potent Cytotoxicity against Diverse Epithelial Cancer Cells

Chang

Gupta

Michel

et al. 2010

Molecular Cancer Therapeutics

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“…176,177 Photochemical internalization enhances endosomal release by means of "photosensitizers", which are agents that translocate through intracellular membranes, e.g., some ribonucleases or toxins. This principle has been extensively studied for immunotoxins or targeted RNases [195][196][197] that both require cell binding and uptake into target cells by a ligand or antibody recognizing internalizing surface receptors. After endocytosis, the toxin or RNase moiety must be transferred into the cytosol in order to engage with their cellular substrates and ultimately cause cell death.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

Targeting antibodies to the cytoplasm

Marschall

Frenzel

Schirrmann

et al. 2011

mAbs

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110

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“…Human Angiogenin is a human plasma protein with 65% homology to RNase A and is one of more than 20 ribonucleases involved in RNA metabolism [20]. In contrast to several other RNase A superfamily members, Angiogenin has been shown to be a potent inhibitor on protein synthesis through digestion of tRNA in cell-free systems [21].…”

Section: Introductionmentioning

confidence: 99%

Species-Dependent Functionality of the Human Cytolytic Fusion Proteins Granzyme B-H22(scFv) and H22(scFv)-Angiogenin in Macrophages

et al. 2013

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Human cytolytic fusion proteins (hCFPs) are comprised of a specific cell-surface-binding moiety and an effector molecule of human origin. In contrast to common immunotoxins, including bacterial or plant toxins, they are considered not to be immunogenic. Two examples for human pro-apoptotic effector proteins are the serine protease Granzyme B and the RNase Angiogenin. Pre-clinical testing of functionality in in vitro and in vivo studies is essential for therapeutics. Establishing relevant animal models that have predictive value for therapeutic success is a great challenge in biomedical research. In this study, we investigated the species-dependent cytotoxic activity of two hCFPs prior to their application in a murine inflammation model. We found that in vitro and ex vivo either hCFP was able to kill human cells only, leaving murine cells unaffected. In contrast, no species-dependency was found for the bacterial Pseudomonas exotoxin A based immunotoxin H22(scFv)-ETA'. This species-dependent functioning has to be carefully considered when performing pre-clinical studies in animal models.

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Targeted therapeutic RNases (ImmunoRNases)

Cited by 53 publications

References 102 publications

Ranpirnase (Frog RNase) Targeted with a Humanized, Internalizing, Anti–Trop-2 Antibody Has Potent Cytotoxicity against Diverse Epithelial Cancer Cells

Ranpirnase (Frog RNase) Targeted with a Humanized, Internalizing, Anti–Trop-2 Antibody Has Potent Cytotoxicity against Diverse Epithelial Cancer Cells

Targeting antibodies to the cytoplasm

Species-Dependent Functionality of the Human Cytolytic Fusion Proteins Granzyme B-H22(scFv) and H22(scFv)-Angiogenin in Macrophages

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