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Updated: Dec 25, 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
Antibody-Drug Conjugates: Patient and Treatment Selection
Shalini Makawita1, Funda Meric-Bernstam1,2
1Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX.
Abstract:
Antibody-drug conjugates (ADCs) are a promising drug platform designed to enhance the therapeutic index and minimize the toxicity of anticancer agents. ADCs have experienced substantial progress and technological growth over the past decades; however, several challenges to patient selection and treatment remain. Methods to optimally capture all patients who may benefit from a particular ADC are still largely unknown. Although target antigen expression remains a biomarker for patient selection, the impact of intratumor heterogeneity on antigen expression, as well as the dynamic changes in expression with treatment and disease progression, are important considerations in patient selection. Better understanding of these factors, as well as minimum levels of target antigen expression required to achieve therapeutic efficacy, will enable further optimization of selection strategies. Other important considerations include understanding mechanisms of primary and acquired resistance to ADCs. Ongoing efforts in the design of its constituent parts to possess the intrinsic ability to overcome these mechanisms, including use of the "bystander effect" to enhance efficacy in heterogeneous or low target antigen-expressing tumors, as well as modulation of the chemical and immunophenotypic properties of antibodies and linker molecules to improve payload sensitivity and therapeutic efficacy, are under way. These strategies may also lead to improved safety profiles. Similarly, combination strategies using ADCs with other cytotoxic or immunomodulatory agents are also under development. Great strides have been made in ADC technology. With further refinements, this therapeutic modality has the potential to make an important clinical impact on a wider range of tumor types.
Insights
Antibody-drug conjugates (ADCs) offer targeted cancer therapy but require improved patient selection. Further research into antigen expression, resistance mechanisms, and combination strategies will enhance ADC efficacy and safety.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Antibody-drug conjugates (ADCs) represent a significant advancement in cancer therapy, aiming to improve efficacy and reduce toxicity.
- Despite progress, challenges persist in identifying optimal patient populations and treatment strategies for ADCs.
- Current patient selection often relies on target antigen expression, but factors like tumor heterogeneity and dynamic expression changes complicate this approach.
Purpose of the Study:
- To review the current state of antibody-drug conjugate (ADC) technology and identify key challenges in patient selection and treatment optimization.
- To explore strategies for overcoming resistance mechanisms and improving the therapeutic index of ADCs.
- To highlight the potential of ADCs in expanding their clinical impact across various cancer types.
Main Methods:
- Literature review of recent advancements in ADC technology, patient selection biomarkers, and resistance mechanisms.
- Analysis of strategies to enhance ADC efficacy, including the bystander effect and payload optimization.
- Discussion of combination therapies involving ADCs and other anticancer agents.
Main Results:
- Target antigen expression is a key biomarker, but intratumor heterogeneity and dynamic expression changes necessitate refined selection methods.
- Understanding and overcoming primary and acquired resistance mechanisms are crucial for maximizing ADC effectiveness.
- Novel ADC design strategies, such as the bystander effect and improved antibody/linker properties, show promise for enhanced efficacy and safety.
Conclusions:
- Further understanding of antigen expression dynamics and resistance mechanisms will optimize patient selection for ADCs.
- Ongoing innovations in ADC design and combination strategies hold significant potential for improving patient outcomes in oncology.
- Antibody-drug conjugate technology is poised to make a substantial clinical impact on a broader spectrum of cancers with continued development.
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