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Updated: Jul 6, 2025
Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018
Exploring the next generation of antibody-drug conjugates
Kyoji Tsuchikama1, Yasuaki Anami2, Summer Y Y Ha2
1Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA. kyoji.tsuchikama@uth.tmc.edu.
Abstract:
Antibody-drug conjugates (ADCs) are a promising cancer treatment modality that enables the selective delivery of highly cytotoxic payloads to tumours. However, realizing the full potential of this platform necessitates innovative molecular designs to tackle several clinical challenges such as drug resistance, tumour heterogeneity and treatment-related adverse effects. Several emerging ADC formats exist, including bispecific ADCs, conditionally active ADCs (also known as probody-drug conjugates), immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs, and each offers unique capabilities for tackling these various challenges. For example, probody-drug conjugates can enhance tumour specificity, whereas bispecific ADCs and dual-drug ADCs can address resistance and heterogeneity with enhanced activity. The incorporation of immune-stimulating and protein-degrader ADCs, which have distinct mechanisms of action, into existing treatment strategies could enable multimodal cancer treatment. Despite the promising outlook, the importance of patient stratification and biomarker identification cannot be overstated for these emerging ADCs, as these factors are crucial to identify patients who are most likely to derive benefit. As we continue to deepen our understanding of tumour biology and refine ADC design, we will edge closer to developing truly effective and safe ADCs for patients with treatment-refractory cancers. In this Review, we highlight advances in each ADC component (the monoclonal antibody, payload, linker and conjugation chemistry) and provide more-detailed discussions on selected examples of emerging novel ADCs of each format, enabled by engineering of one or more of these components.
Insights
Innovative antibody-drug conjugate (ADC) formats like bispecific and probody-drug conjugates offer enhanced tumour targeting and combat drug resistance. Advances in ADC components and design are crucial for effective cancer treatment.
Area of Science:
- Oncology
- Biotechnology
- Drug Development
Background:
- Antibody-drug conjugates (ADCs) are a key cancer therapy, selectively delivering cytotoxic drugs to tumors.
- Clinical challenges like drug resistance, tumor heterogeneity, and adverse effects limit current ADC efficacy.
- Novel ADC designs are needed to overcome these limitations and improve patient outcomes.
Purpose of the Study:
- To review emerging antibody-drug conjugate (ADC) formats and their potential to address clinical challenges in cancer therapy.
- To highlight advances in ADC components (antibody, payload, linker, conjugation chemistry) and their impact on novel ADC development.
- To emphasize the importance of patient stratification and biomarker identification for emerging ADC therapies.
Main Methods:
- Review of current literature on antibody-drug conjugate (ADC) advancements.
- Analysis of emerging ADC formats including bispecific, probody-drug conjugates, immune-stimulating, protein-degrader, and dual-drug ADCs.
- Discussion of engineering strategies for ADC components and their clinical implications.
Main Results:
- Several novel ADC formats (bispecific, probody-drug conjugates, immune-stimulating, protein-degrader, dual-drug) demonstrate unique capabilities.
- Probody-drug conjugates enhance tumor specificity; bispecific and dual-drug ADCs improve activity against resistance and heterogeneity.
- Immune-stimulating and protein-degrader ADCs offer distinct mechanisms for multimodal cancer treatment.
Conclusions:
- Emerging ADC formats hold significant promise for overcoming current treatment limitations in refractory cancers.
- Continued innovation in ADC design, coupled with patient stratification and biomarker identification, is essential for maximizing therapeutic benefits.
- Advancements in ADC components and conjugation chemistry are paving the way for more effective and safer cancer therapies.
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