## 3 Materials and Methods
### Bioconjugation, Purification and Characterization of the ADC 4  
Materials were obtained from commercial suppliers at the highest purity grade available and used without further purification. Disulfide bonds were reduced using a solution of Tris(2-carboxyly)phosphine (TCEP). The BBS conjugation buffer (Borate Buffered Saline) 1X was made at pH 8.0 with 25 mM NaCl, 1 mM EDTA and was titrated with NaOH 1M. The PBS buffer (Phosphate-Buffered Saline) 1X at pH 7.2 was used for the purification step of the ADC. The antibody trastuzumab was provided by le Centre Hospitalier Regional Universitaire (CHRU) de Tours. Antibody trastuzumab and trastuzumab-DNA mimic conjugate concentrations were determined by UV absorbance using NanoDrop-spectrophotometer (Thermo Fisher Scientific).  
Conjugation of trastuzumab with diphenylthio-Mal-Cap-foldamer **3** (Figure 1C) was then performed as follows. To the purified trastuzumab (4.91 mg/mL, 33.16 uM, 10 \(\times\) 200 uL, 148,068 Da) in BBS conjugation buffer was added TCEP (6 equiv, 1 mM in conjugation buffer, 10 \(\times\) 39.79 uL) under argon and the reaction mixture was incubated at 37 \({}^{\circ}\)C for 75 min. Then, a solution of **3** (6 equiv, 1 mM in H\({}_{2}\)O MilliQ, 10 \(\times\) 39.79 uL) was added and the reaction mixture was incubated for 2 h at 4 \({}^{\circ}\)C under stirring at 600 rpm. The crude conjugate was then purified by repeated ultrafiltration (GE Healthcare, 10,000 MWCO) into PBS Buffer (1\(\times\) pH 7.2) and filtered through 0.22 um filters. The purified ADC **4** was obtained at 13.37 uM (2.17 mg/mL). An average DAR of 3.0 was determined by LC-MS analysis according to our previously described method and the formula given below [17; 25].  
Characterization of the ADC **4** was performed by High Resolution Mass Spectrometry using an Acquity UPLC H-Class system hyphenated to a Vion IMS QTof mass spectrometer, both from Waters (Wilmslow, UK). Before MS analysis, 800 ng of sample was injected onto a BEH C4 2.1 \(\times\) 30 mm, 1.7 um column heated to 90\({}^{\circ}\)C. A desalting step was carried on with 95% solvent A (H\({}_{2}\)O + 0.1% formic acid) and 5% solvent B (acetonitrile + 0.1% formic acid) during 2 min at 0.5 mL/min, with the flow diverted to waste. Then, a 4 min gradient from 5% to 90% solvent B was applied with a 0.4 mL/min flow rate to elute the sample with the flow diverted to MS. MS data have been acquired using positive ionization mode with an ESI source over a 500 to 4000 \(m\)/z window with 1 Hz scan. Voltage capillary was set to 2.5 kV, desolvation temperature and source temperature to 600 \({}^{\circ}\)C and 120 \({}^{\circ}\)C, respectively, and cone voltage 150 V. The results were processed using the UNIFI software version 1.9.4 and the MaxEnt1 algorithm for deconvolution. Deconvolution was carried out in the range 20-180 kDa, with results recorded for full antibody as well as fragments when present (comprising H, L, LH and LHH) as a result of antibody dissociation within the MS. The average DAR was calculated as an average of the percentage abundance of each present DAR species, with the quantities calculated by peak integration of the first glycosylation peak, following the general corresponding formula:  
\[DAR_{average}=\frac{DAR_{LHHL}+(DAR_{LHH}+DAR_{L})+2*DAR_{LH}}{3}\]