%0 Journal Article
%T Hydrophilic Auristatin Glycoside Payload Enables Improved Antibody-Drug Conjugate Efficacy and Biocompatibility
%A Anja Vilkman
%A Annamari Heiskanen
%A Bram Herpers
%A Henna PynnŁżnen
%A Jari Helin
%A Juhani Saarinen
%A Leo S. Price
%A Tero Satomaa
%A Titta Kotiranta
%A Virve PitkŁżnen
%J -
%D 2018
%R https://doi.org/10.3390/antib7020015
%X Abstract Antibody-drug conjugates (ADCs) offer a combination of antibody therapy and specific delivery of potent small-molecule payloads to target cells. The properties of the ADC molecule are determined by the balance of its components. The efficacy of the payload component increases with higher drug-to-antibody ratio (DAR), while homogeneous DAR = 8 ADCs are easily prepared by conjugation to the four accessible antibody hinge cystines. However, use of hydrophobic payloads has permitted only DAR = 2¨C4, due to poor pharmacokinetics and aggregation problems. Here, we describe generation and characterization of homogeneous DAR = 8 ADCs carrying a novel auristatin ŚÂ- D-glucuronide, MMAU. The glycoside payload contributed to overall hydrophilicity of the ADC reducing aggregation. Compared to standard DAR = 2¨C4 ADCs, cytotoxicity of the homogeneous DAR = 8 ADCs was improved to low-picomolar IC 50 values against cancer cells in vitro. Bystander efficacy was restored after ADC internalization and subsequent cleavage of the glycoside, although unconjugated MMAU was relatively non-toxic to cells. DAR = 8 MMAU ADCs were effective against target antigen-expressing xenograft tumors. The ADCs were also studied in 3D in vitro patient-derived xenograft (PDX) assays where they outperformed clinically used ADC. In conclusion, increased hydrophilicity of the payload contributed to the ADCĄŻs hydrophilicity, stability and safety to non-target cells, while significantly improving cytotoxicity and enabling bystander efficacy. View Full-Tex
%K glycoside
%K auristatin
%K MMAE
%K MMAU
%K ADC
%K hydrophilicity
%K therapeutic window
%U https://www.mdpi.com/2073-4468/7/2/15