Substrate Design Enables Heterobifunctional, Dual "Click" Antibody Modification via Microbial Transglutaminase.
Bioconjug Chem
; 30(9): 2452-2457, 2019 09 18.
Article
em En
| MEDLINE
| ID: mdl-31409067
Site-specific modification of native antibodies has proven advantageous, as it enhances the properties of antibody-based bioconjugates without the need to manipulate the genetic code. However, native antibody modification is typically limited to strategies that introduce a single functional handle. In this work, we addressed this limitation by designing heterobifunctional substrates for microbial transglutaminase (MTG) that contain both azide and methyltetrazine "click" handles. Structure-conjugation relationships for these substrates were evaluated using the Her2-targeted antibody trastuzumab. Förster resonance energy transfer (FRET) was used to demonstrate that these chemical handles are mutually orthogonal. This orthogonality was leveraged for the one-pot synthesis of a bifunctional antibody-drug conjugate (ADC). This ADC, containing a maytansine-derived payload and a hydrophobicity-masking polyethylene glycol (PEG) side chain, demonstrated potent in vitro activity in SKOV3 cells. These studies establish the dual "click" approach as a powerful technique in the toolbox for native antibody modification.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transglutaminases
/
Imunoconjugados
Limite:
Humans
Idioma:
En
Revista:
Bioconjug Chem
Ano de publicação:
2019
Tipo de documento:
Article