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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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111In-Labeled recombinant gelonin toxin-B lymphocyte stimulator protein fusion protein

[111In]-DTPA-rGel/BLyS
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894

Created: ; Last Update: March 31, 2011.

Chemical name:111In-Labeled recombinant gelonin toxin-B lymphocyte stimulator protein fusion protein
Abbreviated name:[111In]-DTPA-rGel/BLyS
Synonym:TNFSF13b; BAFF; TALL-1; zTNF-4; THANK (for BLyS, from Treml et al. (1))
Agent Category:Fusion protein
Target:BLyS receptor 3 (primary target); transmembrane activator, calcium-modulating cyclophilin ligand interactant, and B-cell maturation antigen receptor (secondary targets)
Target Category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT); gamma planar imaging
Source of signal / contrast:111In
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Structure not available in PubChem.

Background

[PubMed]

The B lymphocyte stimulator (BLyS; for other synonyms see Summary Table above) is a glycoprotein belonging to the tumor necrosis factor cytokine family and promotes the survival, proliferation, and differentiation of the B cells (2). Three different receptors on the B cells (for details, see Wen et al. (2)) are known to bind BLyS; among these, the B cell–activating factor receptor shows the strongest affinity for this cytokine. Although BLyS is overexpressed on B cells of individuals suffering from autoimmune diseases such as lupus, rheumatoid arthritis, etc., the BLyS receptors are known to be expressed on the membrane surface of several types of cancerous tumor cells [PubMed]. Because of its specificity of binding to B cells, BLyS-derived fusion toxins such as the gelonin (Gel)-BLyS fusion protein has been studied by investigators to selectively target and treat B cell malignancies (3-6).

Gel is an N-glycosidase type I ribosome-inactivating plant toxin that lacks a cell binding or a cell internalization domain and is almost non-toxic to intact cells (2, 7). However, mammalian cells can internalize the toxin in association with a carrier, at which point Gel is lethal to the cells because it inhibits protein synthesis completely within 3–4 days of internalization and release within the cell. Recently a recombinant Gel (rGel)-BLyS fusion protein (rGel/BLyS) was constructed by linking rGel to the N-terminus of BLyS, and rGel/BLys was labeled with 111In using diethylenetriamine pentaacetic acid (DTPA) to produce the radionuclide chelator [111In]-DTPA-rGel/BLyS (2). The biodistribution and tumor-imaging characteristics of [111In]-DTPA-rGel/BLyS were then studied in severe combined immunodeficient (SCID) mice bearing B cell lymphoma tumors (2).

Other Sources of Information

Protein and mRNA sequences of human BLyS (tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B).

BLyS in OMIM (Online Mendelian Inheritance in Man Database).

Clinical trials involving BLyS.

Clinical trials with Belimumab (anti-BLyS monoclonal antibody).

Protein and linear DNA (source: Patent US 5624827) sequence of plant toxin gelonin (from Gelonium multiflorum).

Gelonin toxin in PubMed.

What is lupus? Information on MedlinePlus.

Drugs to treat lupus - FDA site.

Lupus in Genome-Wide Association Studies Database.

What is rheumatoid arthritis? Information on Medline Plus.

Drugs to treat rheumatoid arthritis - FDA site.

Rheumatoid arthritis in Genome-Wide Association Studies Database.

Synthesis

[PubMed]

The rGel/BLyS fusion protein was expressed in and purified from Escherichia coli as described elsewhere (3). The fusion protein was conjugated to DTPA and labeled with 111In as detailed by Wen et al. (2). The radiochemical yield of [111In]-DTPA-rGel/BLyS was not reported. Radiochemical purity of the final product was >95% as determined with instant thin-layer chromatography (Rf values were not reported). The specific activity of [111In]-DTPA-rGel/BLyS was up to 0.3 MBq/μg (8.1 μCi/μg).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The in vitro biological activity of rGel/BLyS and the DTPA-rGel/BLyS conjugate was investigated using JeKo-1 cells (a mantle cell lymphoma cell line) and OCI-Ly10 cells (a diffuse large B cell lymphoma cell line) (2). Both constructs showed a similar cytotoxic effect on the two cell lines, indicating that the conjugation of DTPA to rGel/BLyS did not affect the biological activity of the conjugated fusion protein.

Animal Studies

Rodents

[PubMed]

The biodistribution of [111In]-DTPA-rGel/BLyS was studied in SCID mice bearing OCI-Ly10 tumors (2). Five mice received an intravenous injection of the radiochemical (1.85 MBq/6 μg (50 μCi/6 μg)), and 48 h post-injection (p.i.) the animals were euthanized to retrieve the major organs. The amount of radioactivity in each organ was determined and presented as percent injected dose per gram tissue (% ID/g). Maximum label accumulation was detected in the spleen (16.2 ± 3.3% ID/g), followed by the liver (5.4 ± 1.0% ID/g), kidneys (4.0 ± 0.3% ID/g), and bone (1.31 ± 0.4% ID/g). The tumor retained 1.25 ± 0.4% ID/g of the label at 48 h p.i., and the tumor/blood and tumor/muscle ratios were 13.2 and 4.9, respectively.

Micro-SPECT/CT images were acquired from two SCID mice bearing OCI-Ly10 tumors at various predetermined time points for up to 72 h after intravenous injection of [111In]-DTPA-rGel/BLyS (2). From the micro-SPECT/CT images, it was evident that, in addition to the tumor, the radioactivity was present in the liver, kidneys, and bone as observed during the biodistribution study. The tumor was clearly visible at 24 h p.i., and the amount of radioactivity in the lesion was reported to peak at this time point followed by a gradual decrease up to 72 h p.i.

From these studies, the investigators concluded that [111In]-DTPA-rGel/BLyS can be used to detect B-cell tumors in rodents (2).

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

Supplemental Information

[Disclaimers]

No information is currently available.

References

1.
Treml J.F., Hao Y., Stadanlick J.E., Cancro M.P. The BLyS family: toward a molecular understanding of B cell homeostasis. Cell Biochem Biophys. 2009;53(1):1–16. [PMC free article: PMC2654184] [PubMed: 19034695]
2.
Wen, X., M.A. Lyu, R. Zhang, W. Lu, Q. Huang, D. Liang, M.G. Rosenblum, and C. Li, Biodistribution, Pharmacokinetics, and Nuclear Imaging Studies of (111)In-labeled rGel/BLyS Fusion Toxin in SCID Mice Bearing B Cell Lymphoma. Mol Imaging Biol, 2010. [PubMed: 20686856]
3.
Lyu M.A., Cheung L.H., Hittelman W.N., Marks J.W., Aguiar R.C., Rosenblum M.G. The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA. Mol Cancer Ther. 2007;6(2):460–70. [PubMed: 17267661]
4.
Lyu M.A., Rai D., Ahn K.S., Sung B., Cheung L.H., Marks J.W., Aggarwal B.B., Aguiar R.C., Gandhi V., Rosenblum M.G. The rGel/BLyS fusion toxin inhibits diffuse large B-cell lymphoma growth in vitro and in vivo. Neoplasia. 2010;12(5):366–75. [PMC free article: PMC2864474] [PubMed: 20454508]
5.
Lyu M.A., Sung B., Cheung L.H., Marks J.W., Aggarwal B.B., Aguiar R.C., Rosenblum M.G. The rGel/BLyS fusion toxin inhibits STAT3 signaling via down-regulation of interleukin-6 receptor in diffuse large B-cell lymphoma. Biochem Pharmacol. 2010;80(9):1335–42. [PubMed: 20654581]
6.
Yuan X., Lin X., Manorek G., Howell S.B. Challenges associated with the targeted delivery of gelonin to claudin-expressing cancer cells with the use of activatable cell penetrating peptides to enhance potency. BMC Cancer. 2011;11:61. [PMC free article: PMC3042419] [PubMed: 21303546]
7.
Pirie C.M., Hackel B.J., Rosenblum M.G., Wittrup K.D. Convergent Potency of Internalized Gelonin Immunotoxins across Varied Cell Lines, Antigens, and Targeting Moieties. J Biol Chem. 2011;286(6):4165–72. [PMC free article: PMC3039404] [PubMed: 21138845]
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