Modulating Antibody-Drug Conjugate Payload Metabolism by Conjugation Site and Linker Modification

Bioconjugate Chemistry
Dian SuThomas H Pillow

Abstract

Previous investigations on antibody-drug conjugate (ADC) stability have focused on drug release by linker-deconjugation due to the relatively stable payloads such as maytansines. Recent development of ADCs has been focused on exploring technologies to produce homogeneous ADCs and new classes of payloads to expand the mechanisms of action of the delivered drugs. Certain new ADC payloads could undergo metabolism in circulation while attached to antibodies and thus affect ADC stability, pharmacokinetics, and efficacy and toxicity profiles. Herein, we investigate payload stability specifically and seek general guidelines to address payload metabolism and therefore increase the overall ADC stability. Investigation was performed on various payloads with different functionalities (e.g., PNU-159682 analog, tubulysin, cryptophycin, and taxoid) using different conjugation sites (HC-A118C, LC-K149C, and HC-A140C) on THIOMAB antibodies. We were able to reduce metabolism and inactivation of a broad range of payloads of THIOMAB antibody-drug conjugates by employing optimal conjugation sites (LC-K149C and HC-A140C). Additionally, further payload stability was achieved by optimizing the linkers. Coupling relatively stable sites with optimized ...Continue Reading

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May 10, 2019·Pharmaceutics·Eduard FiguerasNorbert Sewald
Mar 21, 2020·SLAS Discovery·Laurence Gauzy-LazoMarie-Priscille Brun
Jan 16, 2020·Antibodies·Donmienne LeungYiqing Feng
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Sep 15, 2021·Bioconjugate Chemistry·Jorick J BruinsBauke Albada

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