Abstract
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 ~75-90% conjugation efficiency is described, resulting from a systematic screening of all relevant reaction parameters. The main unexpected and counterintuitive finding was that 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 which was shown to be perfectly scalable: our lead Lx -ADC was produced on a 5 g scale with an outstanding conjugation efficiency of 89%. This unique metal-based conjugation approach will no doubt show its true value in future clinical trials.
Original language | English |
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Pages (from-to) | 3008-3015 |
Number of pages | 8 |
Journal | Angewandte Chemie International Edition in English |
Volume | 60 |
Issue number | 6 |
Early online date | 13 Nov 2020 |
DOIs | |
Publication status | Published - 8 Feb 2021 |