Unlocking the potential of antibody-drug conjugates for cancer therapy
Joshua Z Drago1,2, Shanu Modi3,4, Sarat Chandarlapaty5,6,7
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Abstract:
Nine different antibody-drug conjugates (ADCs) are currently approved as cancer treatments, with dozens more in preclinical and clinical development. The primary goal of ADCs is to improve the therapeutic index of antineoplastic agents by restricting their systemic delivery to cells that express the target antigen of interest. Advances in synthetic biochemistry have ushered in a new generation of ADCs, which promise to improve upon the tissue specificity and cytotoxicity of their predecessors. Many of these drugs have impressive activity against treatment-refractory cancers, although hurdles impeding their broader use remain, including systemic toxicity, inadequate biomarkers for patient selection, acquired resistance and unknown benefit in combination with other cancer therapies. Emerging evidence indicates that the efficacy of a given ADC depends on the intricacies of how the antibody, linker and payload components interact with the tumour and its microenvironment, all of which have important clinical implications. In this Review, we discuss the current state of knowledge regarding the design, mechanism of action and clinical efficacy of ADCs as well as the apparent limitations of this treatment class. We then propose a path forward by highlighting several hypotheses and novel strategies to maximize the potential benefit that ADCs can provide to patients with cancer.
Insights
Antibody-drug conjugates (ADCs) offer targeted cancer therapy, but challenges like toxicity and resistance persist. Future strategies focus on optimizing ADC design and patient selection for improved efficacy in cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Nine antibody-drug conjugates (ADCs) are approved cancer treatments, with many more in development.
- ADCs aim to enhance the therapeutic index of chemotherapy by targeting cancer cells.
- Newer ADCs leverage synthetic biochemistry for improved tissue specificity and cytotoxicity.
Purpose of the Study:
- To review the current landscape of antibody-drug conjugate (ADC) design, mechanisms, and clinical efficacy.
- To identify limitations hindering broader ADC application in cancer therapy.
- To propose novel strategies for maximizing ADC therapeutic potential.
Main Methods:
- Review of existing literature on antibody-drug conjugates.
- Analysis of ADC design, including antibody, linker, and payload interactions.
- Discussion of clinical efficacy, challenges, and future directions.
Main Results:
- ADCs show promise against refractory cancers but face hurdles: systemic toxicity, patient selection biomarkers, resistance, and combination therapy unknowns.
- ADC efficacy is intricately linked to the interplay between antibody, linker, payload, and the tumor microenvironment.
- Current knowledge highlights the need for refined strategies to overcome existing limitations.
Conclusions:
- Optimizing ADC design and understanding their interaction with the tumor microenvironment are crucial for clinical success.
- Addressing challenges in patient selection and resistance mechanisms will expand ADC utility.
- Further research into novel strategies is essential to fully realize the potential of ADCs in cancer treatment.
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