Generation of DAR1 Antibody-Drug Conjugates for Ultrapotent Payloads Using Tailored GlycoConnect Technology

Area of Science:

• Bioconjugation Chemistry
• Antibody-Drug Conjugate Technology
• Cancer Therapeutics

Background:

• Antibody-drug conjugates (ADCs) typically utilize drug-to-antibody ratios (DARs) of 2-8.
• ADCs with highly potent payloads (e.g., PBD dimers, calicheamicin) require low dosing (<0.5 mg/kg), potentially limiting tumor biodistribution and receptor saturation.
• Current ADC technologies may require antibody re-engineering for lower DARs.

Purpose of the Study:

• To demonstrate the adaptability of GlycoConnect technology for creating DAR1 ADCs without antibody re-engineering.
• To evaluate the efficacy of DAR1 ADCs with ultrapotent cytotoxic payloads.
• To assess the impact of lower DAR on tumor penetration for ADCs with ultrapotent payloads.

Main Methods:

• Adaptation of GlycoConnect technology to generate DAR1 ADCs.
• Demonstration of payload compatibility with the GlycoConnect methodology.
• In vitro assessment of tumor spheroid penetration using AlexaFluor647-labeled DAR1 and DAR2 PBD-based ADCs.

Main Results:

• GlycoConnect technology successfully generated DAR1 ADCs without antibody re-engineering.
• Various ultrapotent cytotoxic payloads were found to be compatible with the methodology.
• DAR1 ADCs showed significantly improved tumor spheroid penetration compared to DAR2 ADCs at equal payload doses.

Conclusions:

• GlycoConnect technology can be extended to create DAR1 ADCs, offering a viable alternative for ADCs with ultrapotent payloads.
• Lowering the DAR to 1 can enhance tumor penetration, potentially overcoming limitations associated with high-potency payload ADCs.
• DAR1 ADCs represent a promising strategy for improving the therapeutic index of antibody-drug conjugates bearing ultrapotent payloads.