A5031750428- Monoclonal and Polyclonal Antibodies Research
- Radiopharmaceutical Chemistry and Applications
- HER2/EGFR in Cancer Research
- Toxin Mechanisms and Immunotoxins
- Enzyme Structure and Function
- Protein Structure and Dynamics
- Advanced NMR Techniques and Applications
- Bacterial Genetics and Biotechnology
- Nanoparticle-Based Drug Delivery
- RNA and protein synthesis mechanisms
- Bacteriophages and microbial interactions
- Ion channel regulation and function
- Viral Infectious Diseases and Gene Expression in Insects
- Peptidase Inhibition and Analysis
- NMR spectroscopy and applications
- Enzyme Production and Characterization
- RNA Interference and Gene Delivery
- Glycosylation and Glycoproteins Research
- DNA Repair Mechanisms
- CAR-T cell therapy research
- Cancer Research and Treatments
- Medical Imaging Techniques and Applications
- Protein purification and stability
- Cancer therapeutics and mechanisms
- Animal Genetics and Reproduction
Institute of Bioorganic Chemistry
2013-2024
National Research Tomsk State University
2019-2024
Tomsk Polytechnic University
2019-2024
Russian Academy of Sciences
1989-2011
Engelhardt Institute of Molecular Biology
1992-2000
BNip3 is a prominent representative of apoptotic Bcl-2 proteins with rather unique properties initiating an atypical programmed cell death pathway resembling both necrosis and apoptosis. Many family modulate the permeability state outer mitochondrial membrane by forming homo- hetero-oligomers. The structure dynamics homodimeric transmembrane domain were investigated aid solution NMR in lipid bicelles molecular energy relaxation explicit bilayer. right-handed parallel helix-helix hydrogen...
Eph receptors are found in a wide variety of cells developing and mature tissues represent the largest family receptor tyrosine kinases, regulating cell shape, movements, attachment. The kinases conduct biochemical signals across plasma membrane via lateral dimerization which their transmembrane domains play an important role. Structural-dynamic properties homodimeric domain EphA1 were investigated with aid solution NMR lipid bicelles molecular dynamics explicit bilayer. segments associate...
When combined with immunotherapy, image-guided targeted delivery of chemotherapeutic agents is a promising direction for combination cancer theranostics, but this approach has so far produced only limited success due to lack molecular targets on the cell surface and low therapeutic index conventional chemotherapy drugs. Here, we demonstrate synergistic strategy immuno/chemotherapy in conditions dual regioselective targeting, implying vectoring two distinct binding sites single oncomarker...
Radionuclide molecular imaging of human epidermal growth factor type 2 (HER2) expression may enable a non-invasive discrimination between HER2-positive and HER2-negative breast cancers for stratification patients HER2-targeted treatments. DARPin G3 is small (molecular weigh 14 kDa) scaffold protein with picomolar affinity to HER2. The aim this first-in-human study was evaluate the safety, biodistribution dosimetry <sup>99m</sup>Tc-(HE)<sub>3</sub>-G3. <b>Methods:</b> Three cohorts primary...
Designed ankyrin repeat proteins (DARPins) are small engineered scaffold that can be selected for binding to desirable molecular targets. High affinity and size of DARPins render them promising probes radionuclide imaging. However, detailed knowledge on many factors influencing their imaging properties is still lacking. We have evaluated two human epidermal growth factor 2 (HER2)-specific with different properties. 9_29-H6 G3-H6 were radiolabeled iodine-125 tricarbonyl technetium-99m in...
Designed ankyrin repeat protein (DARPin) G3 is an engineered scaffold protein. This small (14.5 kDa) targeting binds with high affinity to human epidermal growth factor receptor 2 (HER2). HER2 overexpressed in several cancers. The use of the DARPin for radionuclide therapy complicated by its renal reabsorption after clearance via glomeruli. We tested hypothesis that a fusion albumin-binding domain (ABD) would prevent rapid excretion and resulting better tumour targeting. Two proteins were...
Abstract Radionuclide molecular imaging of HER2 expression in disseminated cancer enables stratification patients for HER2-targeted therapies. DARPin G3, a small (14 kDa) engineered scaffold protein, is promising probe HER2. We hypothesized that position (C- or N-terminus) and composition (hexahistidine (HE) 3 ) histidine-containing tags would influence the biodistribution [ 99m Tc]Tc(CO) -labeled G3. To test hypothesis, G3 variants containing at N-terminus (H 6 -G3 -G3) C-terminus (G3-H...
We report here a combined anti-cancer therapy directed toward HER2 and EpCAM, common tumor-associated antigens of breast cancer cells. The therapeutic effect is achieved owing to two highly toxic proteins-a low immunogenic variant Pseudomonas aeruginosa exotoxin A ribonuclease Barnase from Bacillus amyloliquefaciens. delivery toxins cells was carried out by targeting designed ankyrin repeat proteins (DARPins). have shown that both target agents efficiently accumulate in the tumor....
The development of chimeric antigen receptor (CAR) T cell therapy has become a critical milestone in modern oncotherapy. Despite the remarkable vitro effectiveness, problem safety and efficacy CAR against solid tumors is challenged by lack tumor-specific antigens required to avoid on-target off-tumor effects. Spatially separating cytotoxic function cells from tumor recognition provided protein mediators allows for precise control cytotoxicity. Here, high affinity capability bacterial...
High immunogenicity and systemic toxicity are the main obstacles limiting clinical use of therapeutic agents based on Pseudomonas aeruginosa exotoxin A. In this work, we studied immunogenicity, general antitumor effect targeted toxin DARPin-LoPE composed HER2-specific DARPin a low immunogenic A fragment lacking immunodominant human B lymphocyte epitopes. The has been shown to effectively inhibit growth HER2-positive ovarian carcinoma xenografts, while exhibiting non-specific side effects,...
Previous Phase I clinical evaluations of the radiolabelled scaffold proteins [99mTc]Tc-ADAPT6 and DARPin [99mTc]Tc-(HE)3-G3 in breast cancer patients have demonstrated their safety indicated capability to discriminate between HER2-positive HER2-negative tumours. The objective this study was compare imaging tumours same using [99mTc]Tc-(HE)3-G3. Eleven treatment-naïve female (26–65 years) with primary metastatic were included study. Each patient intravenously injected [99mTc]Tc-ADAPT6,...
Specific interactions between transmembrane α-helices, to a large extent, determine the biological function of integral membrane proteins upon normal development and in pathological states an organism. Various membrane-like media, partially those mimicking conditions multicomponent membranes, are used study structural thermodynamic features that define character oligomerization helical segments. The choice composition membrane-mimicking medium is conducted effort obtain biologically relevant...
A high level of EpCAM overexpression in lung cancer makes this protein a promising target for targeted therapy. Radionuclide visualization expression would facilitate the selection patients potentially benefiting from such treatment. Single-photon computed tomography (SPECT) using 99mTc-labeled engineered scaffold DARPin Ec1 has shown its effectiveness imaging tumors with preclinical studies, providing contrast just few hours after injection. This first-in-human study aimed to evaluate...
Radionuclide-based imaging of molecular therapeutic targets might facilitate stratifying patients for specific biotherapeutics. New type probes, based on designed ankyrin repeat proteins (DARPins), have demonstrated excellent contrast human epidermal growth factor 2 (HER2) expression in preclinical models. We hypothesized that labeling approaches, which result lipophilic radiometabolites (non-residualizing labels), would provide the best DARPins internalize slowly after binding to cancer...
The efficiency of delivering a therapeutic agent into tumor is among the crucial factors determining prospects for its clinical use. This problem particularly acute in case targeted antitumor agents since many them are high-molecular-weight compounds. In this work, penetration two distinct molecular weights spheroids ovarian adenocarcinoma overexpressing human epidermal growth factor receptor 2 (HER2) was studied. It shown that low-molecular-weight chemotherapy drug, doxorubicin (~0.5 kDa),...
Radionuclide molecular imaging of human epidermal growth factor receptor 2 (HER2) in breast and gastroesophageal cancer might be used to stratify patients for HER2-targeted therapy as well monitor treatment response disease progression. Designed ankyrin repeat proteins (DARPins) are small engineered scaffold with favorable properties imaging. Herein we compared two methods labeling the anti-HER2 DARPin (HE)3-G3, direct indirect radioiodination. We hypothesized that use...
Abstract Background Designed ankyrin repeat proteins (DARPins) are small engineered scaffold (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 targeted radionuclide therapy. A better understanding the mechanisms behind kidney uptake could aid development strategies to reduce it. In this study, we have investigated whether [ 99m Tc]Tc(CO) 3 -G3...
Epithelial cell adhesion molecule (EpCAM) is overexpressed in 55%–75% of ovarian carcinomas (OC). EpCAM might be used as a target for treatment disseminated OC. Designed ankyrin repeats protein (DARPin) Ec1 small (18 kDa) protein, which binds to with subnanomolar affinity. We tested hypothesis that labeled non-residualizing label serve companion imaging diagnostic stratification patients EpCAM-targeting therapy. was 125I using N-succinimidyl-para-iodobenzoate. Binding affinity, specificity,...