Homogeneous Dual-Payload Antibody-Drug Conjugates Produced by Combined Distinct Conjugation Strategies.

Area of Science:

• Oncology
• Biotechnology
• Pharmaceutical Sciences

Background:

• Antibody-drug conjugates (ADCs) are advanced targeted cancer therapies.
• Challenges like tumor heterogeneity and resistance limit current ADC efficacy.
• Novel ADC strategies are needed to enhance therapeutic outcomes.

Purpose of the Study:

• To develop homogeneous dual-payload ADCs using site-selective conjugation.
• To combine AJICAP technology and interchain-break conjugation for dual payload delivery.
• To evaluate the efficacy and stability of novel multipayload ADCs.

Main Methods:

• Synthesized dual-payload ADCs using trastuzumab as a model antibody.
• Employed second-generation AJICAP technology and interchain-break conjugation.
• Assessed in vitro cytotoxicity and in vivo tumor suppression in relevant cancer models.

Main Results:

• Successfully created a dual-payload ADC with a drug-to-antibody ratio (DAR) of 10.
• The dual-payload ADC exhibited low aggregation and stable physicochemical properties.
• Demonstrated superior in vitro cytotoxicity and enhanced in vivo tumor suppression compared to controls.

Conclusions:

• Multipayload ADCs show significant potential for enhancing therapeutic efficacy.
• This strategy can help overcome limitations associated with traditional ADCs.
• Dual-payload ADCs represent a promising advancement in targeted cancer therapy.