Antibody-Drug Conjugates Derived from Cytotoxic seco-CBI-Dimer Payloads Are Highly Efficacious in Xenograft Models and Form Protein Adducts In Vivo

  • Bioconjug Chem. 2019 May 15;30(5):1356-1370. doi: 10.1021/acs.bioconjchem.9b00133.
Dian Su  1 ,  Jinhua Chen  2 ,  Ely Cosino  1 ,  Josefa Dela Cruz-Chuh  1 ,  Helen Davis  1 ,  Geoffrey Del Rosario  1 ,  Isabel Figueroa  1 ,  Leanne Goon  1 ,  Jintang He  1 ,  Amrita V Kamath  1 ,  Surinder Kaur  1 ,  Katherine R Kozak  1 ,  Jeffrey Lau  1 ,  Donna Lee  1 ,  M Violet Lee  1 ,  Douglas Leipold  1 ,  Luna Liu  1 ,  Peter Liu  1 ,  Guo-Liang Lu  3 ,  Chris Nelson  1 ,  Carl Ng  1 ,  Thomas H Pillow  1 ,  Paul Polakis  1 ,  Andrew G Polson  1 ,  Rebecca K Rowntree  1 ,  Ola Saad  1 ,  Brian Safina  1 ,  Nicola J Stagg  1 ,  Moana Tercel  3 ,  Richard Vandlen  1 ,  Breanna S Vollmar  1 ,  John Wai  2 ,  Tao Wang  2 ,  BinQing Wei  1 ,  Keyang Xu  1 ,  Juanjuan Xue  2 ,  Zijin Xu  2 ,  Gang Yan  2 ,  Hui Yao  2 ,  Shang-Fan Yu  1 ,  Donglu Zhang  1 ,  Fiona Zhong  1 ,  Peter S Dragovich  1
Affiliations
  • 1. Genentech Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
  • 2. WuXi AppTec Co., Ltd. , 288 Fute Zhong Road , Waigaoqiao Free Trade Zone, Shanghai 200131 , China.
  • 3. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences , The University of Auckland , Private Bag 92019, Auckland 1142 , New Zealand.
PMID: 30966735 DOI: 10.1021/acs.bioconjchem.9b00133
Abstract

This work discloses the first examples of antibody-drug conjugates (ADCs) that are constructed from linker-drugs bearing dimeric seco-CBI payloads (duocarmycin analogs). Several homogeneous, CD22-targeting THIOMAB antibody-drug conjugates (TDCs) containing the dimeric seco-CBI entities are shown to be highly efficacious in the WSU-DLCL2 and BJAB mouse xenograft models. Surprisingly, the seco-CBI-containing conjugates are also observed to undergo significant biotransformation in vivo in mice, rats, and monkeys and thereby form 1:1 adducts with the Alpha-1-Microglobulin (A1M) plasma protein from these species. Variation of both the payload mAb attachment site and length of the linker-drug is shown to alter the rates of adduct formation. Subsequent experiments demonstrated that adduct formation attenuates the in vitro antiproliferation activity of the affected seco-CBI-dimer TDCs, but does not significantly impact the in vivo efficacy of the conjugates. In vitro assays employing phosphatase-treated whole blood suggest that A1M adduct formation is likely to occur if the seco-CBI-dimer TDCs are administered to humans. Importantly, protein adduct formation leads to the underestimation of total antibody (Tab) concentrations using an ELISA assay but does not affect Tab values determined via an orthogonal LC-MS/MS method. Several recommendations regarding bioanalysis of future in vivo studies involving related seco-CBI-containing ADCs are provided based on these collective findings.

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