An Efficient Conjugation Approach for Coupling Drugs to Native Antibodies via the PtII Linker Lx for Improved Manufacturability of Antibody–Drug Conjugates

Eugen Merkul*, Joey A. Muns, Niels J. Sijbrandi, Hendrik-Jan Houthoff, Bart Nijmeijer, Gerro van Rheenen, Jan Reedijk, Guus A. M. S. van Dongen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
Pages (from-to)3008-3015
Number of pages8
JournalAngewandte Chemie International Edition in English
Volume60
Issue number6
Early online date13 Nov 2020
DOIs
Publication statusPublished - 8 Feb 2021

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