Related Experiment Video
Updated: Nov 1, 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
Uncialamycin-based antibody-drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect
K C Nicolaou1, Stephan Rigol2, Emmanuel N Pitsinos2,3
1BioScience Research Collaborative, Department of Chemistry, Rice University, Houston, TX 77005; kcn@rice.edu julia.gavrilyuk@gmail.com.
Abstract:
Antibody-drug conjugates (ADCs) have emerged as valuable targeted anticancer therapeutics with at least 11 approved therapies and over 80 advancing through clinical trials. Enediyne DNA-damaging payloads represented by the flagship of this family of antitumor agents, N-acetyl calicheamicin [Formula: see text], have a proven success track record. However, they pose a significant synthetic challenge in the development and optimization of linker drugs. We have recently reported a streamlined total synthesis of uncialamycin, another representative of the enediyne class of compounds, with compelling synthetic accessibility. Here we report the synthesis and evaluation of uncialamycin ADCs featuring a variety of cleavable and noncleavable linkers. We have discovered that uncialamycin ADCs display a strong bystander killing effect and are highly selective and cytotoxic in vitro and in vivo.
Insights
New antibody-drug conjugates (ADCs) using the enediyne compound uncialamycin show potent anticancer activity. These targeted therapies demonstrate significant bystander killing effects, selectivity, and cytotoxicity in preclinical studies.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Antibody-drug conjugates (ADCs) are a successful class of targeted anticancer therapeutics, with multiple agents approved and many more in clinical development.
- Enediyne compounds, such as N-acetyl calicheamicin, are potent DNA-damaging agents used as payloads in ADCs, but their synthesis can be challenging.
- Uncialamycin, another enediyne, has recently become synthetically accessible, presenting an opportunity for novel ADC development.
Purpose of the Study:
- To synthesize and evaluate antibody-drug conjugates (ADCs) utilizing the enediyne compound uncialamycin.
- To investigate the impact of different linker types (cleavable and non-cleavable) on the efficacy of uncialamycin ADCs.
- To assess the in vitro and in vivo anticancer activity, including bystander killing effects, selectivity, and cytotoxicity, of these novel ADCs.
Main Methods:
- Synthesis of uncialamycin and its conjugation to antibodies via various cleavable and non-cleavable linkers.
- In vitro cytotoxicity assays to determine the potency of uncialamycin ADCs against cancer cell lines.
- In vivo studies to evaluate the therapeutic efficacy, selectivity, and bystander killing potential of the developed ADCs.
Main Results:
- The synthesized uncialamycin ADCs demonstrated potent and selective cytotoxicity against cancer cells in vitro.
- These ADCs exhibited a significant bystander killing effect, indicating their ability to eliminate neighboring tumor cells.
- Preclinical in vivo evaluations confirmed the high efficacy and selectivity of uncialamycin ADCs.
Conclusions:
- Uncialamycin-based ADCs represent a promising new class of targeted anticancer agents.
- The synthetic accessibility of uncialamycin facilitates the development of novel ADC therapeutics.
- Uncialamycin ADCs show potential for clinical application due to their potent cytotoxicity and bystander effect.
More Related Videos
Related Concept Videos
01:26Antibody Actions
Neutralization
Antibodies can bind to pathogens, preventing them from infecting host cells. This process...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...