Figure 1.

(A) Schematic representation of a site-specific ADC comprising the anti-HER2 trastuzumab conjugated to a polyanionic foldamer via a diphenylthio-maleimido-caproic acid linker (diphenyltio-Mal-Cap) with a DAR of 3 (drug-to-antibody ratio, corresponding to the number of foldamers grafted onto the mAb). (B) Coupling reaction performed on solid phase between the protected foldamer 1 and the diphenylthio-Mal-Cap linker 2 to produce the diphenylthio-Mal-Cap-foldamer polyanionic 3 after resin cleavage and side chain deprotection. (C) The ADC 4 was obtained by complete reduction (TCEP) of all four interchain disulfide bridges followed by a site-specific bioconjugation reaction via a diphenylthio-Mal-Cap linker 2. During the foldamer solid phase synthesis and the coupling reaction shown in (B), the phosphonate groups of the quinoline monomers are protected as tert-butyl esters. TCEP = tris(2-carboxyethyl)phosphine.