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

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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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Merkul, E., Muns, J. A., Sijbrandi, N. J., Houthoff, H. J., Nijmeijer, B., van Rheenen, G., … van Dongen, G. A. M. S. (2021). An Efficient Conjugation Approach for Coupling Drugs to Native Antibodies via the PtII Linker Lx for Improved Manufacturability of Antibody–Drug Conjugates. Angewandte Chemie - International Edition, 60(6), 3008–3015. https://doi.org/10.1002/anie.202011593

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