In Vitro and In Vivo Evaluation of Cysteine Rebridged Trastuzumab–MMAE Antibody Drug Conjugates with Defined Drug-to-Antibody Ratios

• DOI: 10.1021/acs.molpharmaceut.5b00116
• Publication Date: 2015-04-20T14:06:00Z
• Authors: Penny Bryant; Martin Pabst; George Badescu; Matthew Bird; William McDowell; Estera Jamieson; Julia Swierkosz; Kosma Jurlewicz; Rita Tommasi; Korinna Henseleit; XiaoBo Sheng; Nicolas Camper; Anais Manin; Katarzyna Kozakowska; Karolina Peciak; Emmanuelle Laurine; Ruslan Grygorash; Andrew Kyle; David Morris; Vimal Parekh; Amrita Abhilash; Ji-won Choi; Jeff Edwards; Mark Frigerio; Matthew P. Baker; Antony Godwin
• Keywords: Conjugate; Antibody-drug conjugate; Internalization; Linker

The conjugation of monomethyl auristatin E (MMAE) to trastuzumab using a reduction bis-alkylation approach that is capable rebridging reduced (native) antibody interchain disulfide bonds has been previously shown produce homogeneous and stable conjugate with drug-to-antibody ratio (DAR) 4 as the major product. Here, we further investigate potency DAR conjugates prepared by comparing lower drug loaded variants maleimide linker based possessing typical mixed profiles. Serum stability, HER2 receptor binding, internalization, in vitro potency, vivo efficacy were all evaluated. Greater stability compared was observed no significant decrease receptor/FcRn binding. A clear dose-response obtained on loading showing highest much higher conjugates. Finally, demonstrated superior trastuzumab-DM1 (T-DM1, Kadcyla), evaluated low expressing JIMT-1 xenograft model.