An efficient conjugation approach for coupling drugs to native antibodies via the PtII linker Lx for improved manufacturability of antibody–drug conjugates

Merkul, E.; Muns, J.A.; Sijbrandi, N.J.; Houthoff, H.‐J.; Nijmeijer, B.; Rheenen, G. van; ... ; Dongen, G.A.M.S. van (2020)

Article / Letter to editor

The Pt-II linker [ethylenediamineplatinum(II)](2+), coined Lx, has emerged as a novel non-conventional approach to antibody-drug conjugates (ADCs) and has shown its potential in preclinical in vitro and in vivo benchmark studies. A crucial improvement of the Lx conjugation reaction from initially <15 % to ca. 75-90 % conjugation efficiency is described, resulting from a systematic screening of all relevant reaction parameters. NaI, a strikingly simple inorganic salt additive, greatly improves the conjugation efficiency as well as the conjugation selectivity simply by exchanging the leaving chloride ligand on Cl-Lx-drug complexes (which are direct precursors for Lx-ADCs) for iodide, thus generating I-Lx-drug complexes as more reactive species. Using this iodide effect, we developed a general and highly practical conjugation procedure that is scalable: our lead Lx-ADC was produced on a 5 g scale with an outstanding conjugation efficiency of 89 %.

• All authors: Merkul, E.; Muns, J.A.; Sijbrandi, N.J.; Houthoff, H.‐J.; Nijmeijer, B.; Rheenen, G. van; Reedijk, J.; Dongen, G.A.M.S. van
• Date: 2020-11-13
• Journal: Angewandte Chemie International Edition
• Volume: 60
• Issue: 6
• Pages: 3008 - 3015
• DOI: doi:10.1002/anie.202011593
• Link: http://dx.doi.org/10.1002/anie.202011593