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JOURNAL ARTICLE

Antibody-drug Conjugates Derived From Cytotoxic seco-CBI-Dimer Payloads are Highly Efficacious in Xenograft Models and Form Protein Adducts In Vivo

Dian Su, Jinhua Chen, Ely Cosino, Josefa Dela Cruz-Chuh, Helen Davis, Geoffrey Del Rosario, Isabel Figueroa, Leanne Goon, Jintang He, Amrita Kamath, Surinder Kaur, Katherine Kozak, Jeffrey Lau, Donna Lee, M Violet Lee, Doug Leipold, Luna Liu, Peter Liu, Guo-Liang Lu, Chris Nelson, Carl Ng, Thomas Pillow, Paul Polakis, Andrew Gorham Polson, Rebecca K Rowntree, Ola M Saad, Brian Safina, Nicola Stagg, Moana Tercel, Richard Vandlen, Breanna S Vollmar, John Wai, Tao Wang, Keyang Xu, Juanjuan Xue, Zijin Xu, Yan Gang, Hui Yao, Shang-Fan Yu, Donglu Zhang, Fiona Zhong, Peter S Dragovich, Binqing Wei
Bioconjugate Chemistry 2019 April 10
30966735
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 THIOMABTM 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 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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