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Antibodies 2018, 7(2), 15;

Hydrophilic Auristatin Glycoside Payload Enables Improved Antibody-Drug Conjugate Efficacy and Biocompatibility

Glykos Finland Ltd., FI-00790 Helsinki, Finland
OcellO B.V., 2333 CH Leiden, The Netherlands
Authors to whom correspondence should be addressed.
Received: 15 December 2017 / Revised: 1 March 2018 / Accepted: 5 March 2018 / Published: 22 March 2018
(This article belongs to the Special Issue Antibody Drug Conjugates)
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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 = 2–4, due to poor pharmacokinetics and aggregation problems. Here, we describe generation and characterization of homogeneous DAR = 8 ADCs carrying a novel auristatin β-D-glucuronide, MMAU. The glycoside payload contributed to overall hydrophilicity of the ADC reducing aggregation. Compared to standard DAR = 2–4 ADCs, cytotoxicity of the homogeneous DAR = 8 ADCs was improved to low-picomolar IC50 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 ADC’s hydrophilicity, stability and safety to non-target cells, while significantly improving cytotoxicity and enabling bystander efficacy. View Full-Text
Keywords: glycoside; auristatin; MMAE; MMAU; ADC; hydrophilicity; therapeutic window glycoside; auristatin; MMAE; MMAU; ADC; hydrophilicity; therapeutic window

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Satomaa, T.; Pynnönen, H.; Vilkman, A.; Kotiranta, T.; Pitkänen, V.; Heiskanen, A.; Herpers, B.; Price, L.S.; Helin, J.; Saarinen, J. Hydrophilic Auristatin Glycoside Payload Enables Improved Antibody-Drug Conjugate Efficacy and Biocompatibility. Antibodies 2018, 7, 15.

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