Optimal composition and position of histidine-containing tags improves biodistribution of 99mTc-labeled DARPin G3

Vorobyeva, Anzhelika; Schulga, Alexey; Коновалова, Е. В.; Güler, Rezan; Löfblom, John; Sandström, Mattias; Garousi, Javad; Chernov, Vladimir; Bragina, Olga; Orlova, Anna; Tolmachev, Vladimir; Deyev, Sergey M.

doi:10.1038/s41598-019-45795-8

Cited by 40 publications

(65 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A new class of targeting molecules, engineered scaffold proteins (ESPs), is promising agents for tumor-targeted delivery of radionuclides [1]. Several types of ESPs, such as affibody molecules [2], ADAPTs [3], and DARPins [4][5][6][7][8][9] demonstrated efficient tumor targeting and high contrast of radionuclide imaging in preclinical studies. DARPins are built of 4-6 repeat modules of 33 amino acids and have a molecular weight of 14-18 kDa [10].…”

Section: Introductionmentioning

confidence: 99%

On the prevention of kidney uptake of radiolabeled DARPins

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background: Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins (14-18 kDa) that demonstrated promising tumor-targeting properties in preclinical studies. However, high renal accumulation of activity for DARPins labeled with residualizing labels is a limitation for targeted radionuclide therapy. A better understanding of the mechanisms behind the kidney uptake of DARPins could aid the development of strategies to reduce it. In this study, we have investigated whether the renal uptake of [ 99m Tc]Tc(CO) 3-G3 DARPin could be reduced by administration of compounds that act on various parts of the reabsorption system in the kidney. Results: Co-injection of lysine or Gelofusine was not effective for the reduction of kidney uptake of [ 99m Tc]Tc(CO) 3-G3. Administration of sodium maleate before the injection of [ 99m Tc]Tc(CO) 3-G3 reduced the kidney-associated activity by 60.4 ± 10.3%, while administration of fructose reduced it by 46.9 ± 7.6% compared with the control. The decrease in the kidney uptake provided by sodium maleate was also observed for [ 99m Tc]Tc(CO) 3-9_29 DARPin. Preinjection of colchicine, probenecid, mannitol, or furosemide had no effect on the kidney uptake of [ 99m Tc]Tc(CO) 3-G3. Kidney autoradiography showed mainly cortical accumulation of activity for all studied groups. Conclusion: Common clinical strategies were not effective for the reduction of kidney uptake of [ 99m Tc]Tc(CO) 3-G3. Both fructose and maleate lower the cellular ATP level in the proximal tubule cells and their reduction of the kidney reuptake indicates the involvement of an ATP-driven uptake mechanism. The decrease provided by maleate for both G3 and 9_29 DARPins indicates that their uptake proceeds through a mechanism independent of DARPin structure and binding site composition.

show abstract

Section: Introductionmentioning

confidence: 99%

On the prevention of kidney uptake of radiolabeled DARPins

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…DARPins have both of these properties and can be successfully utilized for the radioactive imaging of tumors. For example, HER2-specific DARPins G3 and 9_29 were used for obtaining conjugates with the desired pharmacokinetics and reduced accumulation in the liver [47][48][49]. As for cancer therapy, DARPins can be used both for the delivery of toxic modules and for the inhibition of cell signaling pathways thanks to the specific binding of membrane receptors.…”

Section: Applications Of Darpins In Cancer Diagnosis and Therapymentioning

confidence: 99%

DARPins: Promising Scaffolds for Theranostics

Shilova

Deyev

2019

Acta Naturae

View full text Add to dashboard Cite

Monoclonal antibodies are the classical basis for targeted therapy, but the development of alternative binding proteins has made it possible to use non-immunoglobulin proteins as targeting modules. The advantages of DARPins, scaffold proteins based on ankyrin repeats, over antibodies are as follows: small size, stability over a wide range of temperatures and pH values, low aggregation tendency, and ease of production in heterologous expression systems. The differences in the structure of the paratope of DARPin and antibodies broaden the spectrum of target molecules, while the ease of creating hybrid fusion proteins allows one to obtain bispecific and multivalent constructs. In this article, we summarize recent data on the development of therapeutic and imaging compounds based on DARPins.

show abstract

“…It was shown that the IL-37-IL-1R8-IL-18Rα complex is assembled on the cell surface, and that its presence is necessary for further triggering of an anti-inflammatory response [46]. The IL-1R8 receptor consists of only one extracellular Ig-like domain with a long "tail" immersed in the cytoplasm and containing a mutant TIR domain [47]. The involvement of IL-1R8 in the anti-inflammatory action of IL-37 has been demonstrated in experiments on mice defective in the gene for this chain.…”

Section: Il-37 Receptor Complex and Signaling Pathwaysmentioning

confidence: 99%

The Role of Interleukin-37 in the Pathogenesis of Allergic Diseases

Shilovskiy¹,

Dyneva²,

Курбачева³

et al. 2019

Acta Naturae

View full text Add to dashboard Cite

Cytokines of the interleukin-1 (IL-1) family play an important role in the realization of the protective functions of innate immunity and are the key mediators involved in the pathogenesis of a wide range of diseases, including various manifestations of allergy. The IL-1 family includes more than 11 members. However, the functions of many of them remain to be elucidated. Recently, new members of the IL-1 family have been discovered. In 2000, several independent research groups reported the discovery of a new interleukin of this family, which was named IL-37, or IL-1F7 (according to the new nomenclature). IL-37 was assigned to the IL-1 family based on its structural similarity with other members of this family. The study of its biological properties showed that its activity changes in inflammatory diseases, such as rheumatoid arthritis, psoriasis, as well as allergic diseases (allergic rhinitis, bronchial asthma, and atopic dermatitis). However, unlike most members of the IL-1 family, IL-37 acts as a negative regulator of inflammation. Activation of IL-37 suppresses inflammation, resulting in the suppression of inflammatory cytokines and chemokines, which in turn prevents infiltration of pro-inflammatory cells, mainly eosinophils and neutrophils. The exact molecular and cellular mechanisms of the anti-inflammatory effect of IL-37 in the development of allergic diseases (AD) have not been fully studied. This review summarizes and analyzes the accumulated experimental data on the role of IL-37 in the pathogenesis of AD, such as allergic rhinitis, bronchial asthma, and atopic dermatitis.

show abstract

Optimal composition and position of histidine-containing tags improves biodistribution of 99mTc-labeled DARPin G3

Cited by 40 publications

References 39 publications

On the prevention of kidney uptake of radiolabeled DARPins

On the prevention of kidney uptake of radiolabeled DARPins

DARPins: Promising Scaffolds for Theranostics

The Role of Interleukin-37 in the Pathogenesis of Allergic Diseases

Contact Info

Product

Resources

About