Cytotoxic ribonuclease chimeras. Targeted tumoricidal activity in vitro and in vivo.

Newton, Dianne L.; Ilercil, Orhan; Laske, Douglas W.; Oldfield, Edward H.; Rybak, Susanna M.; Youle, Richard J.

doi:10.1016/s0021-9258(18)41813-3

Cited by 52 publications

(7 citation statements)

References 38 publications

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“…These enzymes should be most active when delivered to the cytoplasm, but experimental data demonstrate that barnase in the form of a targeted recombinant protein that binds to the surface HER2 receptor enters the cell via receptor-mediated endocytosis and can induce apoptosis in cancer cells [ 112 , 113 ], although the mechanism of its escape from endosome remains unclear. Similar results were obtained for conjugates of mammalian RNAse A with antibodies to transferrin receptor or CD5 tested on cancer cells expressing respective target molecules [ 125 ]. Cytotoxic activity was even shown for untargeted ribonucleases, namely RNAse A, and its homolog onconase, which are likely to be transported to cancer cells in a non-specific manner [ 126 ].…”

Section: Cytotoxic Mechanisms Of Natural Toxinssupporting

confidence: 80%

Natural and Designed Toxins for Precise Therapy: Modern Approaches in Experimental Oncology

Shilova

Шрамова

Прошкина

et al. 2021

IJMS

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Cancer cells frequently overexpress specific surface receptors providing tumor growth and survival which can be used for precise therapy. Targeting cancer cell receptors with protein toxins is an attractive approach widely used in contemporary experimental oncology and preclinical studies. Methods of targeted delivery of toxins to cancer cells, different drug carriers based on nanosized materials (liposomes, nanoparticles, polymers), the most promising designed light-activated toxins, as well as mechanisms of the cytotoxic action of the main natural toxins used in modern experimental oncology, are discussed in this review. The prospects of the combined therapy of tumors based on multimodal nanostructures are also discussed.

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Section: Cytotoxic Mechanisms Of Natural Toxinssupporting

confidence: 80%

Natural and Designed Toxins for Precise Therapy: Modern Approaches in Experimental Oncology

Shilova

Шрамова

Прошкина

et al. 2021

IJMS

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“…Importantly, the potency of the RNase immunofusions is markedly improved compared to RNase chemical conjugates. Bovine pancreatic RNase A conjugated to 454A12, an antihuman transferrin receptor monoclonal antibody, inhibited protein synthesis in human leukemia cells with an IC 50 of 600 nM (Newton et al, 1992) compared to IC 50s between 4 and 10 nM for the most potent AngsFv. These concentrations compared favorably to concentrations needed to achieve 50% protein synthesis inhibition of antitransferrin receptor conjugates made with plant or bacterial toxins such as gelonin (2-5 nM) (Yazdi et al, 1995) or fusion proteins with the same E6sFv and either PE40 or CRM107 (IC 50 , 0.1 and 1 nM, respectively) (Nicholls et al, 1993).…”

Section: Discussionmentioning

confidence: 98%

“…Noncytotoxic members of the ribonuclease (RNase) 1 A superfamily have been linked to tumor-associated cell-surface binding ligands by chemical Newton et al, 1992) or recombinant methods (Rybak et al, 1992;Newton et al, 1994) for the purpose of selectively killing tumor cells while exhibiting fewer side effects than current strategies employing plant and bacterial toxins . Single chain antibodies (sFvs) composed of the variable heavy and light chains of an antibody connected by a peptide linker have been produced in bacteria (Huston et al, 1988;Bird et al, 1988).…”

mentioning

confidence: 99%

Angiogenin Single-Chain Immunofusions: Influence of Peptide Linkers and Spacers between Fusion Protein Domains

et al. 1996

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The gene for human angiogenin (Ang), a member of the ribonuclease superfamily, was fused to a gene encoding a single-chain antibody (sFv) against the human transferrin receptor. Three Ang single-chain immunofusion proteins (AngsFvs) were constructed with variations in the type of linker connecting the VL and VH chain [EGKSSGSGSESKEF, L1 or (GGGGS)3, L2] as well as with or without a spacer (FB) connecting the Ang and sFv (AngFBsFvL1 or L2; AngsFv(L2)]. Although the nature of the linker did not affect the enzymatic activity of the FB-containing fusion proteins, the fusion protein containing the L2 linker was 2.3-fold more effective than the L1 linker in competing with the labeled monoclonal IgG1 antibody for binding to the transferrin receptor. The fusion protein containing the L2 linker without the FB spacer exhibited a 13-fold decrease in binding to the transferrin receptor as well as a decrease in its capacity to degrade tRNA and to inhibit translation in the rabbit reticulocyte lysate compared to its counterpart containing the FB spacer. Binding of placental ribonuclease inhibitor (PRI) to Ang also was affected by the nature of the linker and by the presence or absence of a spacer. PRI bound to Ang and AngFBsFv(L2) and inhibited their ribonuclease activity. A 3-fold greater concentration of PRI, however, did not affect the activity of AngFBsFv(L1) or AngsFv(L2), suggesting that the conformation of these fusion proteins was altered. Binding of monoclonal and polyclonal anti-Ang antibodies to AngsFvs was also used to investigate conformational alterations of the fusion proteins. AngFBsFv(L2) was the least altered while AngFBsFv(L1) exhibited the greatest change in structure. Yet maximal concentrations of all AngsFvs elicited angiogenesis in the chick chorioallantoic membrane assay, demonstrating that Ang in all three fusion proteins remained functionally active. Consistent with all the activities, the fusion protein containing the FB spacer and L2 linker was the most cytotoxic to three different human tumor cell lines. The fusion protein lacking the FB spacer exhibited the least cytotoxicity. These data demonstrate that the linker connecting the VH-VL chains can affect the binding and cellular cytotoxicity of Ang immunofusions and that placement of a spacer between the antibody binding domains and Ang is necessary for optimal activity. Thus, a new class of targeted therapeutic agents containing Ang as the toxic moiety can be designed that potentially will be less immunogenic and less toxic than immunotoxins available currently.

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“…However, as a result of rapid renal filtration of this small enzyme (half-life < 5 min) [47], multiple administrations of high doses of RNase A are essential to reach the required concentration in tumors, which primarily leads to accumulation of this protein in the kidneys. Local administration of protein in tumors reduces the side effects but the therapeutic efficacy remains poor due to insufficient permeability for cell membranes [48,49]. Hence, the development of an effective delivery system that stabilizes the administered RNase A and promotes the cellular association and internalization is highly desirable [50][51][52].…”

Section: Introductionmentioning

confidence: 99%

Polyethyleneimine coated nanogels for the intracellular delivery of RNase A for cancer therapy

Kordalivand

Beztsinna

et al. 2018

Chemical Engineering Journal

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Cytotoxic ribonuclease chimeras. Targeted tumoricidal activity in vitro and in vivo.

Cited by 52 publications

References 38 publications

Natural and Designed Toxins for Precise Therapy: Modern Approaches in Experimental Oncology

Natural and Designed Toxins for Precise Therapy: Modern Approaches in Experimental Oncology

Angiogenin Single-Chain Immunofusions: Influence of Peptide Linkers and Spacers between Fusion Protein Domains

Polyethyleneimine coated nanogels for the intracellular delivery of RNase A for cancer therapy

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