posted on 2023-11-14, 16:34authored byIrene Shajan, Léa N. C. Rochet, Shannon R. Tracey, Bianka Jackowska, Rania Benazza, Oscar Hernandez-Alba, Sarah Cianférani, Christopher J. Scott, Floris L. van Delft, Vijay Chudasama, Bauke Albada
Bispecific antibodies as T cell engagers designed to
display binding
capabilities to both tumor-associated antigens and antigens on T cells
are considered promising agents in the fight against cancer. Even
though chemical strategies to develop such constructs have emerged,
a method that readily converts a therapeutically applied antibody
into a bispecific construct by a fully non-genetic process is not
yet available. Herein, we report the application of a biogenic, tyrosine-based
click reaction utilizing chemoenzymatic modifications of native IgG1
antibodies to generate a synthetic bispecific antibody construct that
exhibits tumor-killing capability at picomolar concentrations. Control
experiments revealed that a covalent linkage of the different components
is required for the observed biological activities. In view of the
highly potent nature of the constructs and the modular approach that
relies on convenient synthetic methods utilizing therapeutically approved
biomolecules, our method expedites the production of potent bispecific
antibody constructs with tunable cell killing efficacy with significant
impact on therapeutic properties.