Back to Search
Start Over
Minibody-Based and scFv-Based Antibody Fragment-Drug Conjugates Selectively Eliminate GD2-Positive Tumor Cells
- Source :
- International Journal of Molecular Sciences; Volume 24; Issue 2; Pages: 1239
- Publication Year :
- 2023
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2023.
-
Abstract
- 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.
- Subjects :
- Inorganic Chemistry
Organic Chemistry
antibody fragments
scFv fragments
minibodies
antibody-drug conjugates
ganglioside GD2
immunotherapy
cancer
GD2-positive tumors
neuroblastoma
melanoma
General Medicine
Physical and Theoretical Chemistry
Molecular Biology
Spectroscopy
Catalysis
Computer Science Applications
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences; Volume 24; Issue 2; Pages: 1239
- Accession number :
- edsair.doi.dedup.....e726fa50e723fc9f1d5c2294f92c7f5e
- Full Text :
- https://doi.org/10.3390/ijms24021239