Multimerization through Pegylation Improves Pharmacokinetic Properties of scFv Fragments of GD2-Specific Antibodies
| Autor: | R. V. Kholodenko, Elena V. Svirshchevskaya, Maria Konovalova, Tatyana V. Shamanskaya, Sergey S. Larin, Igor Doronin, Alexey V. Kibardin, I. V. Kholodenko, Daniel V. Kalinovsky, Sergey M. Deyev |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_treatment
ganglioside GD2 Pharmaceutical Science Article Analytical Chemistry Polyethylene Glycols lcsh:QD241-441 03 medical and health sciences neuroblastoma Mice 0302 clinical medicine Antineoplastic Agents Immunological lcsh:Organic chemistry Pharmacokinetics Neuroblastoma Cell Line Tumor Gangliosides Drug Discovery medicine Cytotoxic T cell multimerization cancer Animals Humans pegylation Physical and Theoretical Chemistry 030304 developmental biology 0303 health sciences antibody fragments Mice Inbred BALB C Ganglioside biology Chemistry Organic Chemistry Immunotherapy Neoplasms Experimental medicine.disease Biochemistry Chemistry (miscellaneous) 030220 oncology & carcinogenesis biology.protein PEGylation Molecular Medicine immunotherapy Antibody Conjugate Single-Chain Antibodies |
| Zdroj: | Molecules Molecules, Vol 24, Iss 21, p 3835 (2019) Volume 24 Issue 21 |
| ISSN: | 1420-3049 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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