Substrate Design Enables Heterobifunctional, Dual "Click" Antibody Modification via Microbial Transglutaminase.
BIOCONJUGATE CHEMISTRY(2019)
摘要
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. Forster 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.
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关键词
antibody modification,substrate design enables heterobifunctional
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