TY - JOUR
T1 - An Efficient Conjugation Approach for Coupling Drugs to Native Antibodies via the PtII Linker Lx for Improved Manufacturability of Antibody–Drug Conjugates
AU - Merkul, Eugen
AU - Muns, Joey A.
AU - Sijbrandi, Niels J.
AU - Houthoff, Hendrik-Jan
AU - Nijmeijer, Bart
AU - van Rheenen, Gerro
AU - Reedijk, Jan
AU - van Dongen, Guus A. M. S.
N1 - Publisher Copyright: © 2020 Wiley-VCH GmbH Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/2/8
Y1 - 2021/2/8
N2 - 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.
AB - 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.
KW - Lx
KW - antibody–drug conjugates
KW - conjugation
KW - linkers
KW - platinum
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85099392546&origin=inward
U2 - https://doi.org/10.1002/anie.202011593
DO - https://doi.org/10.1002/anie.202011593
M3 - Article
C2 - 33185916
SN - 1433-7851
VL - 60
SP - 3008
EP - 3015
JO - Angewandte Chemie International Edition in English
JF - Angewandte Chemie International Edition in English
IS - 6
ER -