Exatecan Payload-Based Antibody-Drug Conjugates with a Short Hydrophilic Cleavable Linker

Area of Science:

• Bioconjugation Chemistry
• Antibody-Drug Conjugate Development
• Pharmacology

Background:

• Antibody-drug conjugates (ADCs) link cytotoxins to antibodies for targeted cancer therapy.
• Hydrophobicity of ADCs can lead to aggregation and poor pharmacokinetics, limiting efficacy.
• Developing hydrophilic linkers is crucial for next-generation ADC design.

Purpose of the Study:

• To design and characterize novel hydrophilic linkers and spacers for ADCs.
• To evaluate the in vitro and in vivo performance of ADCs with these novel linkers.

Main Methods:

• Generation of cathepsin and glucuronidase-cleavable linkers with a hydrophilic 1-amino-β-d-glucuronic acid spacer.
• Conjugation of hydrophilic linker-payloads (exatecan) to trastuzumab (HER-2 antibody).
• Assessment of ADC hydrophilicity, in vitro cytotoxicity, plasma stability, and in vivo efficacy in a mouse xenograft model.

Main Results:

• ADCs with the novel amino-glucuronic acid spacer and glucuronide linker (AV-L03) demonstrated superior hydrophilicity compared to a GGFG linker.
• The AV-L03 linker-exatecan payload ADC (AV-DL055) showed potent in vitro cytotoxicity.
• Improved plasma stability and remarkable in vivo efficacy were observed for AV-DL055 compared to a control ADC.

Conclusions:

• Novel hydrophilic linkers and spacers can overcome the limitations of hydrophobic ADCs.
• The developed glucuronidase-cleavable linker (AV-L03) offers improved hydrophilicity, stability, and in vivo efficacy.
• This approach holds promise for enhancing the therapeutic potential of antibody-drug conjugates.