Design and application of diabodies, triabodies and tetrabodies for cancer targeting

Todorovska, Aneta; Roovers, Rob C.; Dolezal, Olan; Kortt, Alexander A.; Hoogenboom, Hennie R.; Hudson, Peter J.

doi:10.1016/s0022-1759(00)00342-2

Cited by 246 publications

(143 citation statements)

References 82 publications

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“…The kidney retention of radiopharmaceuticals is not only dependent on the characteristics of the targeting molecule itself, but is also dependent on the type of chelator or radionuclides and on the stability of the radiolabeled compound (25,26 3 ] þ easily changes its three water molecules for a wide variety of donor ligands including histidine to form a stable complex. Here we have shown that 99m Tc7C12 is extremely stable in vitro in human serum while in kidneys the radiotracer is metabolized to some extent.…”

Section: Discussionmentioning

confidence: 99%

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Localization, mechanism and reduction of renal retention of technetium‐99m labeled epidermal growth factor receptor‐specific nanobody in mice

Gainkam

Caveliers

Devoogdt

et al. 2010

Contrast Media & Molecular

115

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Background: Nanobodies are single-domain antigen binding fragments derived from functional heavy-chain antibodies elicited in Camelidae. They are powerful probes for radioimmunoimaging, but their renal uptake is relatively high. In this study we have evaluated the role of megalin on the renal uptake of anti-EGFR 99m Tc-7C12 nanobody and the potency of gelofusine and/or lysine to reduce renal uptake of 99m Tc-7C12. Methods: First we compared the renal uptake of 99m Tc-7C12 in megalin-deficient and megalin-wild-type mice using pinhole SPECT/microCT and ex vivo analysis. The effect of gelofusine and lysine administration on renal accumulation of 99m Tc-7C12 was analyzed in CD-1 mice divided into lysine preload at 30 min before tracer injection (LysPreload), LysPreload R gelofusine coadministration (LysPreload R GeloCoad), lysine coadministration (LysCoad), gelofusine coadministration (GeloCoad) and LysCoad R GeloCoad. The combined effect of gelofusine and lysine on tumor uptake was tested in mice xenografts. Results: Renal uptake of 99m Tc-7C12 was 44.22 W 3.46% lower in megalin-deficient compared with megalinwild-type mice. In CD-1 mice, lysine preload had no effect on the renal retention whereas coinjection of lysine or gelofusine with the tracer resulted in 25.12 W 2.99 and 36.22 W 3.07% reduction, respectively. The combined effect of gelofusine and lysine was the most effective, namely a reduction of renal retention of 45.24 W 2.09%. Gelofusine and lysine coadministration improved tumor uptake. Conclusion: Megalin contributes to the renal accumulation of 99m Tc-7C12. Gelofusine and lysine coinjection with the tracer reduces the renal uptake while tumor uptake is improved. Although this methodology allows for optimization of imaging protocol using nanobodies, further improvements are needed before using these molecules for radionuclide therapy.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, coupling with therapeutic radionuclides allows targeted radionuclide therapy. Many different formats have been investigated including nanobodies, minibodies, diabodies (1)(2)(3)(4), scFvs, Fabs and F(ab)2 (5,6). Each format has its own pharmacokinetic profile with a blood clearance that is largely dependent on the molecular size.…”

Section: Introductionmentioning

confidence: 99%

Localization, mechanism and reduction of renal retention of technetium‐99m labeled epidermal growth factor receptor‐specific nanobody in mice

Gainkam

Caveliers

Devoogdt

et al. 2010

Contrast Media & Molecular

115

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“…It has been described that further shortening the linker to less than three residues promotes the formation of molecules with three or four antigen binding sites, ''triabodies'' or ''tetrabodies'', respectively [28]. Linker dependent oligomerization behavior of the murine anti-neuraminidase scFv NC10 [29] has been studied in detail.…”

Section: Discussionmentioning

confidence: 99%

Antigen binding and stability properties of non‐covalently linked anti‐CD22 single‐chain Fv dimers

Arndt¹,

Krauß²,

Rybak³

2004

FEBS Letters

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By varying linker length and domain orientation three multivalent derivatives of a monovalent anti-CD22 single-chain fragment variable (scFv) antibody were generated. Shortening the linker of the V H -V L oriented scFv to 5 or 0 residues resulted in the formation of diabodies or a mixture of tetramers and trimers, respectively. Unexpectedly, a V L -0-V H scFv assembled to homogenous dimers, remained substantially more stable than the V H -5-V L diabody when incubated in human serum at 37°C, and retained its dimeric state when concentrated up to 4 mg/ml. These properties suggest the V L -0-V H scFv could become an attractive vehicle for the selective delivery of multiple effector molecules to CD22 + tumor cells.

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“…Fourthly, because the molecular weight of scFv-Fc is about two third of intact antibody, this molecule will penetrate into the center of solid tumor more rapidly and get increased tumor distribution compared to the whole Ig without fast renal clearance. Thereby it will exert greater effect on tu-mor tissue [27]. Moreover, because of it single-gene structure, it will be very easy to conjugate this molecule with other effectors such as cytokines and immunotoxin by fused with their genes.…”

Section: Discussionmentioning

confidence: 99%

Construction, expression and characterization of the engineered antibody against tumor surface antigen, p185c-erbB-2

et al. 2003

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The c-erbB-2 proto-oncogene encodes a 185kDa protein p185, which belongs to epidermal growth factor receptor family. Amplification of this gene has been shown to correlate with poor clinical prognosis for certain cancer patients. The monoclonal antibody A21 which directed against p185 specifically inhibits proliferation of tumor cells overexpressing p185, hence allows it to be a candidate for targeted therapy. In order to overcome several drawbacks of murine MAb, we cloned its VH and VL genes and constructed the single-chain Fv (scFv) through a peptide linker. The recombinant scFvA21 was expressed in Escherichia coli and purified by the affinity column. Subsequently it was characterized by ELISA, Western blot, cell immunohistochemistry and FACS. All these assays showed the binding activity to extracellular domain (ECD) of p185. Based on those properties of scFvA21, we further constructed the scFv-Fc fusion molecule with a homodimer form and the recombinant product was expressed in mammalian cells. In a series of subsequent analysis this fusion protein showed identical antigen binding site and activity with the parent antibody. These anti-p185 engineered antibodies have promised to be further modified as a tumor targeting drugs, with a view of application in the diagnosis and treatment of human breast cancer.

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Design and application of diabodies, triabodies and tetrabodies for cancer targeting

Cited by 246 publications

References 82 publications

Localization, mechanism and reduction of renal retention of technetium‐99m labeled epidermal growth factor receptor‐specific nanobody in mice

Localization, mechanism and reduction of renal retention of technetium‐99m labeled epidermal growth factor receptor‐specific nanobody in mice

Antigen binding and stability properties of non‐covalently linked anti‐CD22 single‐chain Fv dimers

Construction, expression and characterization of the engineered antibody against tumor surface antigen, p185c-erbB-2

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