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  • Title: An Efficient Conjugation Approach for Coupling Drugs to Native Antibodies via the PtII Linker Lx for Improved Manufacturability of Antibody-Drug Conjugates.
    Author: Merkul E, Muns JA, Sijbrandi NJ, Houthoff HJ, Nijmeijer B, van Rheenen G, Reedijk J, van Dongen GAMS.
    Journal: Angew Chem Int Ed Engl; 2021 Feb 08; 60(6):3008-3015. PubMed ID: 33185916.
    Abstract:
    The PtII 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 %.
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