Strategies and challenges for the next generation of antibody–drug conjugates

  title={Strategies and challenges for the next generation of antibody–drug conjugates},
  author={Alain Beck and Liliane Goetsch and Charles Dumontet and Nathalie Corvaïa},
  journal={Nature Reviews Drug Discovery},
Antibody–drug conjugates (ADCs) are one of the fastest growing classes of oncology therapeutics. After half a century of research, the approvals of brentuximab vedotin (in 2011) and trastuzumab emtansine (in 2013) have paved the way for ongoing clinical trials that are evaluating more than 60 further ADC candidates. The limited success of first-generation ADCs (developed in the early 2000s) informed strategies to bring second-generation ADCs to the market, which have higher levels of cytotoxic… 
Recent Chemical Approaches for Site‐Specific Conjugation of Native Antibodies: Technologies toward Next‐Generation Antibody–Drug Conjugates
  • Kei Yamada, Yuji Ito
  • Biology, Chemistry
    Chembiochem : a European journal of chemical biology
  • 2019
Various site‐specific chemical conjugation strategies with native mAbs that are currently used for the production ofADCs, including residue‐selective labeling for generating ADCs, disulfide rebridging, and affinity‐peptide‐mediated site‐ Specific Conjugation technologies, are reviewed and described.
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The present review explores ADCs, their main characteristics, and new research developments, as well as discusses strategies for the selection of the most appropriate target antigens, mAbs, cytotoxic drugs, linkers, and conjugation chemistries.
Challenges of Antibody Drug Conjugates in Cancer Therapy: Current Understanding of Mechanisms and Future Strategies
This manuscript is a comprehensive review of the up-to-date knowledge on mechanism of action of ADCs, key factors that affect the safety and efficacy ofADCs, and the challenges and new strategies associated with rational design of ADC.
Unlocking the potential of antibody–drug conjugates for cancer therapy
The authors discuss the design and mechanisms of action of ADCs and how these properties are reflected in the clinical activity and toxicity profiles of such agents and propose a path forward by highlighting several hypotheses and novel strategies to maximize the potential benefit that ADCs can provide to patients with cancer.
Benefits and challenges of antibody drug conjugates as novel form of chemotherapy.
Structure-Activity Relationships of Antibody-Drug Conjugates: A Systematic Review of Chemistry on the Trastuzumab Scaffold.
The anti-HER-2 antibody trastuzumab, first approved in 1998, has emerged as an exceptional targeting agent for ADCs, as well as a broadly used platform for testing new technologies, to enable the comparison of existing and emerging conjugate technologies.
Antibody-Drug Conjugates: Functional Principles and Applications in Oncology and Beyond
This paper summarizes the essential components of ADCs, from their functional principles and structure up to their limitations and resistance mechanisms, focusing on all latest bioengineering breakthroughs such as bispecific mAbs, dual-drug platforms as well as novel linkers and conjugation chemistries.
Antibody-drug conjugates for the treatment of lymphoma: clinical advances and latest progress
An overview of the essential elements of ADC strategies in lymphoma is provided and the up-to-date progress, current challenges, and novel targets of ADCs in this rapidly evolving field are elucidated.
Advances and Limitations of Antibody Drug Conjugates for Cancer
This review summarizes marketed and recently approved ADCs, compares the features of various linker designs and payloads commonly used for ADC conjugation, and outlines cancer specific ADCs that are currently in late-stage clinical trials for the treatment of cancer.
Pharmacokinetic and Immunological Considerations for Expanding the Therapeutic Window of Next-Generation Antibody–Drug Conjugates
Practical considerations for tracking ADC efficacy and toxicity are reviewed, as aided by high-resolution biomolecular and immunological tools, quantitative pharmacology, and mathematical models, all of which can elucidate the relative contributions of the multitude of interactions governing the ADC therapeutic window.


Antibody-targeted drugs and drug resistance--challenges and solutions.
Emerging formats for next-generation antibody drug conjugates
ADCs are at the beginning of the next stage in their evolution and as these newer formats are developed and examined in the clinic, it is envisaged that smaller or fragment-based ADCs will expand oncological applications.
Evolving Strategies for Target Selection for Antibody-Drug Conjugates
The tumor and normal tissue expression profiles of the targets of ADCs currently in clinical development are surveyed, demonstrating a surprisingly broad range of expression profiles and the inability to formalize any optimal parameters for an ADC target.
Site-specific antibody drug conjugates for cancer therapy
Various site-specific conjugation strategies that are currently used for the production of ADCs are reviewed, including use of engineered cysteine residues, unnatural amino acids, and enzymatic conjugations through glycotransferases and transglutaminases.
Antibody-Drug Conjugates for Tumor Targeting-Novel Conjugation Chemistries and the Promise of non-IgG Binding Proteins.
Recent progress with site-specific and biorthogonal conjugation chemistries are delineated, and alternative, biophysically more stable protein scaffolds like Designed Ankyrin Repeat Proteins (DARPins), which may provide such additional engineering opportunities for drug conjugates with improved pharmacological performance are discussed.
Potent antibody drug conjugates for cancer therapy.
  • P. Senter
  • Biology
    Current opinion in chemical biology
  • 2009
The next generation of antibody-drug conjugates comes of age.
Potential benefits of antibody-drug conjugates (ADCs), strategies, and development challenges are discussed in this review and several examples of ADCs are presented with emphasis on three major molecules currently in late clinical development as well as next generation thio-mAbs conjugate with improved therapeutic index.
Antibody-drug conjugates for non-oncological indications
This editorial focuses on the recent development of ADCs for non-oncological indications such as immune modulation and anti-infection and describes a biodegradable anti-CD163 ADC that specifically delivers synthetic glucocorticoid to macrophages.
Antibody-drug conjugates: targeted drug delivery for cancer.