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Published on: September 14, 2018
Homogeneous Dual-Payload Antibody-Drug Conjugates Produced by Combined Distinct Conjugation Strategies
Tomohiro Watanabe1, Yusuke Iwai2, Jason T Stofleth1
1Ajinomoto Bio-Pharma Services, 11040 Roselle Street, San Diego, California 92121, United States.
Abstract:
Antibody-drug conjugates (ADCs) represent a promising class of targeted cancer therapies, combining monoclonal antibody specificity with cytotoxic drug potency. Despite significant ADC technology advancements, challenges such as limited efficacy, often attributed to tumor heterogeneity and resistance development, remain present. In this study, we developed homogeneous dual-payload ADCs by combining site-selective conjugation methods: second-generation AJICAP technology for lysine modification and conventional interchain-break conjugation. Using trastuzumab as a model antibody, we successfully synthesized a drug-to-antibody ratio (DAR) of 10 (2 + 8) dual-payload ADC with monomethyl auristatin E and deruxtecan, displaying low aggregation and stable physicochemical properties. The dual-payload ADC exhibited superior in vitro cytotoxicity against HER2-positive SKBR-3 cells, compared to T-DXd, and demonstrated enhanced tumor suppression in vivo in a NCI-N87 xenograft model. These results highlight the potential of multipayload ADCs in enhancing therapeutic efficacy while maintaining stability, thereby providing a new strategy to overcome traditional ADC-related limitations.
Insights
This study introduces dual-payload antibody-drug conjugates (ADCs) for improved cancer therapy. These novel ADCs demonstrate enhanced efficacy and tumor suppression, offering a new strategy against cancer resistance.
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.
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