Research Topic

The Advancements of Linker Design in Antibody-Drug Conjugates

About this Research Topic

Antibody Drug Conjugates (ADCs) are at the forefront of new technology applications and exploit the specificity of the antibody for targeted delivery of a potent cytotoxic warhead. Whilst simple in concept, ADCs have multiple components and a multi-step mechanism of action with specific requirements for each component and step, and optimizing these aspects in parallel is critical to the success of ADC drug development programs.

Recent ADC clinical trials failures can be directly attributed as a design issue, either through instability of the linker leading to early payload release or non-specific targeting of the ADC driven by the antibody effector function. These failures have highlighted the need to build appropriate linker architectural design into the early stages of the product candidate selection process. The developability approach to ADC lead candidate selection ensures an appropriate de-risking strategy is applied.

Linker design has more recently focused on addressing the issues of instability, heterogeneity and site-specificity to reduce overall ADC toxicity, and the scope of this Research Topic is to detail how new and novel linker modalities that are being developed are leading efforts in these areas. Using native or engineered sites for antibody conjugation of a suitable warhead, details of suitable ADC drug development advances are anticipated to be incorporated into this article series.

In this Research Topic, we aim to publish high-quality manuscripts highlighting novel approaches to ADC linker designs for appropriate bioconjugation. We welcome manuscript submissions in the form of Original Research, Communication and Perspectives. While Review Articles will also be welcomed, they will be considered as long as they sufficiently outline data that can shed light on new perspectives into novel approaches for such designs. The below sub-topics would be welcomed:

- Strategies for improving ADC therapeutic indices through linker designs
- ADC chemical linker design strategies to attach novel payloads
- The influence of conjugation strategy and payload choice on linker design
- ADC linker designs that modulate solubility, drug loading and overall pharmacokinetic (PK)
- Modification to ADC linker chemical functionalities to optimize bioconjugation efficiencies;
- Original approaches to intracellular and tumour microenvironment release mechanisms of payloads from ADCs;
- Enhancing biophysical stability of ADCs through a linker developability approach;
- Reducing ADC safety liabilities through linker payload enhancements


Topic Editors Dr Frigerio and Dr Camper are in full time employment at Abzena, a privately owned contract research organization based in Cambridge UK. All other Topic Editors declare no competing interests with regards to the Research Topic subject. 


Keywords: ADC, conjugation, linker, design, developability


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Antibody Drug Conjugates (ADCs) are at the forefront of new technology applications and exploit the specificity of the antibody for targeted delivery of a potent cytotoxic warhead. Whilst simple in concept, ADCs have multiple components and a multi-step mechanism of action with specific requirements for each component and step, and optimizing these aspects in parallel is critical to the success of ADC drug development programs.

Recent ADC clinical trials failures can be directly attributed as a design issue, either through instability of the linker leading to early payload release or non-specific targeting of the ADC driven by the antibody effector function. These failures have highlighted the need to build appropriate linker architectural design into the early stages of the product candidate selection process. The developability approach to ADC lead candidate selection ensures an appropriate de-risking strategy is applied.

Linker design has more recently focused on addressing the issues of instability, heterogeneity and site-specificity to reduce overall ADC toxicity, and the scope of this Research Topic is to detail how new and novel linker modalities that are being developed are leading efforts in these areas. Using native or engineered sites for antibody conjugation of a suitable warhead, details of suitable ADC drug development advances are anticipated to be incorporated into this article series.

In this Research Topic, we aim to publish high-quality manuscripts highlighting novel approaches to ADC linker designs for appropriate bioconjugation. We welcome manuscript submissions in the form of Original Research, Communication and Perspectives. While Review Articles will also be welcomed, they will be considered as long as they sufficiently outline data that can shed light on new perspectives into novel approaches for such designs. The below sub-topics would be welcomed:

- Strategies for improving ADC therapeutic indices through linker designs
- ADC chemical linker design strategies to attach novel payloads
- The influence of conjugation strategy and payload choice on linker design
- ADC linker designs that modulate solubility, drug loading and overall pharmacokinetic (PK)
- Modification to ADC linker chemical functionalities to optimize bioconjugation efficiencies;
- Original approaches to intracellular and tumour microenvironment release mechanisms of payloads from ADCs;
- Enhancing biophysical stability of ADCs through a linker developability approach;
- Reducing ADC safety liabilities through linker payload enhancements


Topic Editors Dr Frigerio and Dr Camper are in full time employment at Abzena, a privately owned contract research organization based in Cambridge UK. All other Topic Editors declare no competing interests with regards to the Research Topic subject. 


Keywords: ADC, conjugation, linker, design, developability


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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Submission Deadlines

15 July 2020 Abstract
15 November 2020 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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Topic Editors

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Submission Deadlines

15 July 2020 Abstract
15 November 2020 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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