Chemical Production of Cytotoxic Bispecific Antibodies Using the Ugi Multicomponent Reaction.

Fiche publication

Date publication

mai 2024

Journal

Chembiochem : a European journal of chemical biology

Auteurs

Membres identifiés du Cancéropôle Est :
Dr CIANFERANI Sarah , Dr DETAPPE Alexandre , Dr CHAUBET Guilhem

Tous les auteurs :
Vaur V, Koutsopetras I, Erb S, Jackowska B, Benazza R, Cahuzac H, Detappe A, Hernandez-Alba O, Cianférani S, Scott CJ, Chaubet G

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/38713134

Résumé

Bispecific antibodies (bsAbs) have recently emerged as a promising platform for the treatment of several conditions, most importantly cancer. Based on the combination of two different antigen-binding motifs in a single macromolecule; bsAbs can either display the combined characteristics of their parent antibodies, or new therapeutic features, inaccessible by the sole combination of two distinct antibodies. While bsAbs are traditionally produced by molecular biology techniques, the chemical development of bsAbs holds great promises and strategies have just begun to surface. In this context, we took advantage of a chemical strategy based on the use of the Ugi reaction for the site-selective conjugation of whole antibodies and coupled the resulting conjugates in a bioorthogonal manner with Fab fragments, derived from various antibodies. We thus managed to produce five different bsAbs with 2:1 valency, with yields ranging from 20% to 48%, and showed that the affinity of the parent antibody was preserved in all bsAbs. We further demonstrated the interest of our strategy by producing two other bsAbs behaving as cytotoxic T cell engagers with IC50 values in the picomolar range in vitro.