Hydrophilic Auristatin Glycoside Payload Enables Improved Antibody-Drug Conjugate Efficacy and Biocompatibility
AbstractAntibody-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
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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.
Satomaa T, Pynnönen H, Vilkman A, Kotiranta T, Pitkänen V, Heiskanen A, Herpers B, Price LS, Helin J, Saarinen J. Hydrophilic Auristatin Glycoside Payload Enables Improved Antibody-Drug Conjugate Efficacy and Biocompatibility. Antibodies. 2018; 7(2):15.Chicago/Turabian Style
Satomaa, Tero; Pynnönen, Henna; Vilkman, Anja; Kotiranta, Titta; Pitkänen, Virve; Heiskanen, Annamari; Herpers, Bram; Price, Leo S.; Helin, Jari; Saarinen, Juhani. 2018. "Hydrophilic Auristatin Glycoside Payload Enables Improved Antibody-Drug Conjugate Efficacy and Biocompatibility." Antibodies 7, no. 2: 15.
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