Generation of DAR1 Glycosite-Specific Antibody-Drug Conjugates Using DisacLink Technology

Area of Science:

• Bioconjugation Chemistry
• Antibody-Drug Conjugates (ADCs)
• Drug Delivery Systems

Background:

• The drug-to-antibody ratio (DAR) is a critical quality attribute for antibody-drug conjugates (ADCs).
• Conventional site-specific conjugation methods yield ADCs with DAR values typically between 2 and 8.
• Lower DAR values are desirable for enhanced tumor penetration and safety with ultrapotent payloads and for optimized pharmacokinetics in antibody-oligonucleotide conjugates (AOCs).

Purpose of the Study:

• To develop a novel glycosite-specific method for generating antibody-drug conjugates (ADCs) with a drug-to-antibody ratio (DAR) of 1.
• To leverage the previously established DisacLink technology for creating DAR1 ADCs.

Main Methods:

• Utilized bis-functionalized drug-linkers with the DisacLink technology platform.
• Employed synthetic LacNAc oxazoline derivatives for glycosite-specific conjugation.
• Applied the method to major human IgG subclasses and common cytotoxic payloads.

Main Results:

• Successfully generated site-specific DAR1 ADCs with high conjugation efficiency.
• Demonstrated applicability across major human IgG subclasses and various payloads.
• Characterized conjugates for homogeneity, thermal stability, and aggregation resistance.
• Showcased potent in vitro and in vivo antitumor activity of the resulting DAR1 ADCs.

Conclusions:

• The developed bis-functionalized drug-linkers enable efficient generation of glycosite-specific DAR1 ADCs.
• These DAR1 ADCs exhibit favorable stability and potent anti-tumor efficacy.
• This advancement offers a promising strategy for optimizing ADC therapeutics, particularly those utilizing ultrapotent payloads.