Chitosan nanoparticles targeted to the tumor-associated ganglioside GD2

Zubareva, A. A.; Boyko, Anna A.; Холоденко, И. В.; Rozov, F. N.; Larina, M. V.; Алиев, Т. К.; Doronin, Igor I.; Vishnyakova, Polina; Molotkovskaya, I. M.; Холоденко, Р. В.

doi:10.1134/s1068162016050150

Cited by 7 publications

(7 citation statements)

References 25 publications

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“…The transfection efficiency was approx. 20 mg/L, and the stability of the isolated protein was higher compared with the scFv fragments of GD2-specific antibodies which we had previously obtained in E. coli [17].…”

Section: Resultsmentioning

confidence: 99%

“…SDS-PAGE and western blot analysis of non-modified and conjugated scFv fragments were performed as described before [17]. In brief, the samples were resolved in 12% reducing SDS-PAGE, and the resultant gels were either stained with Coomassie R250 or transferred onto nitrocellulose membranes using the Semi-Dry Blotter V10-SDB (Biostep, Burkhardtsdorf, Germany).…”

Section: Methodsmentioning

confidence: 99%

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Multimerization through Pegylation Improves Pharmacokinetic Properties of scFv Fragments of GD2-Specific Antibodies

et al. 2019

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Antigen-binding fragments of antibodies specific to the tumor-associated ganglioside GD2 are well poised to play a substantial role in modern GD2-targeted cancer therapies, however, rapid elimination from the body and reduced affinity compared to full-length antibodies limit their therapeutic potential. In this study, scFv fragments of GD2-specific antibodies 14.18 were produced in a mammalian expression system that specifically bind to ganglioside GD2, followed by site-directed pegylation to generate mono-, di-, and tetra-scFv fragments. Fractionated pegylated dimers and tetramers of scFv fragments showed significant increase of the binding to GD2 which was not accompanied by cross-reactivity with other gangliosides. Pegylated multimeric di-scFvs and tetra-scFvs exhibited cytotoxic effects in GD2-positive tumor cells, while their circulation time in blood significantly increased compared with monomeric antibody fragments. We also demonstrated a more efficient tumor uptake of the multimers in a syngeneic GD2-positive mouse cancer model. The findings of this study provide the rationale for improving therapeutic characteristics of GD2-specific antibody fragments by multimerization and propose a strategy to generate such molecules. On the basis of multimeric antibody fragments, bispecific antibodies and conjugates with cytotoxic drugs or radioactive isotopes may be developed that will possess improved pharmacokinetic and pharmacodynamic properties.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Multimerization through Pegylation Improves Pharmacokinetic Properties of scFv Fragments of GD2-Specific Antibodies

et al. 2019

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“…Product purity and stability were analyzed by size-exclusion chromatography, as described above, and by gel electrophoresis. Visualization of the naked antibody fragments and the FDCs by SDS-PAGE was performed either in reducing or in non-reducing conditions, with modifications to [ 33 ]. For reducing electrophoresis, proteins in standard SDS sample buffer containing 50 mM dithiothreitol were heated to 95 °C for either 5 or 10 min and loaded onto the gels.…”

Section: Methodsmentioning

confidence: 99%

Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells

Kalinovsky

Холоденко

Kibardin

et al. 2023

IJMS

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Ganglioside GD2 is a well-established target expressed on multiple solid tumors, many of which are characterized by low treatment efficiency. Antibody-drug conjugates (ADCs) have demonstrated marked success in a number of solid tumors, and GD2-directed drug conjugates may also hold strong therapeutic potential. In a recent study, we showed that ADCs based on the approved antibody dinutuximab and the drugs monomethyl auristatin E (MMAE) or F (MMAF) manifested potent and selective cytotoxicity in a panel of tumor cell lines and strongly inhibited solid tumor growth in GD2-positive mouse cancer models. Here, we employed two different GD2-binding moieties–minibodies and scFv fragments that carry variable antibody domains identical to those of dinutuximab, and site-directly conjugated them to MMAE or MMAF by thiol-maleimide chemistry with drug-to-antibody ratios (DAR) of 2 and 1, respectively. Specific binding of the antibody fragment-drug conjugates (FDCs) to GD2 was confirmed in direct ELISA, flow cytometry, and confocal microscopy. Selective cytotoxic and cytostatic effects of the conjugates were observed in GD2-positive but not GD2-negative neuroblastoma and melanoma cell lines. Minibody-based FDCs demonstrated more pronounced cytotoxic effects and stronger antigen binding compared to scFv-based FDCs. The developed molecules may offer considerable practical benefit, since antibody fragment-drug conjugates are capable of enhancing therapeutic efficacy of ADCs by improving their pharmacokinetic characteristics and reducing side effects.

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“…As part of immunoconjugates or targeted nanoparticles, full-length GD2-specific antibodies and their fragments act as vectors that specifically bind tumor cells. GD2-binding molecules are used to create GD2-directed liposomes [ 234 – 236 ] and nanoparticles [ 237 – 240 ], combinations of anti-GD2 antibodies with chemokines [ 241 ], cytokines [ 242 ], toxins [ 243 – 246 ], and radioisotopes [ 199 , 247 ]. Antigen-binding antibody fragments have important advantages for use in immunoconjugates over full-length antibodies and lack a number of their disadvantages, such as poor penetration into solid tumors and Fc-mediated hyperactivation of the immune system [ 248 ].…”

Section: Tumor Markers In Neuroblastomamentioning

confidence: 99%

“…In our work, targeted chitosan nanoparticles specific to GD2-positive tumor cells were obtained. Monoclonal GD2-specific antibodies and their Fab and scFv fragments were used as vector molecules, and it was shown that scFv fragments site-specifically conjugated to nanoparticles have a higher antitumor potential compared to full-length antibodies and their Fab fragments [ 240 ].…”

Section: Tumor Markers In Neuroblastomamentioning

confidence: 99%

Neuroblastoma Origin and Therapeutic Targets for Immunotherapy

Холоденко

Kalinovsky

Doronin

et al. 2018

Journal of Immunology Research

127

106

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Neuroblastoma is a pediatric solid cancer of heterogeneous clinical behavior. The unique features of this type of cancer frequently hamper the process of determining clinical presentation and predicting therapy effectiveness. The tumor can spontaneously regress without treatment or actively develop and give rise to metastases despite aggressive multimodal therapy. In recent years, immunotherapy has become one of the most promising approaches to the treatment of neuroblastoma. Still, only one drug for targeted immunotherapy of neuroblastoma, chimeric monoclonal GD2-specific antibodies, is used in the clinic today, and its application has significant limitations. In this regard, the development of effective and safe GD2-targeted immunotherapies and analysis of other potential molecular targets for the treatment of neuroblastoma represents an important and topical task. The review summarizes biological characteristics of the origin and development of neuroblastoma and outlines molecular markers of neuroblastoma and modern immunotherapy approaches directed towards these markers.

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Chitosan nanoparticles targeted to the tumor-associated ganglioside GD2

Cited by 7 publications

References 25 publications

Multimerization through Pegylation Improves Pharmacokinetic Properties of scFv Fragments of GD2-Specific Antibodies

Multimerization through Pegylation Improves Pharmacokinetic Properties of scFv Fragments of GD2-Specific Antibodies

Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells

Neuroblastoma Origin and Therapeutic Targets for Immunotherapy

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