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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
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Generation and Characterization of Iduronidase-Cleavable ADCs
Sebastian Jäger1, Doreen Könning1, Nicolas Rasche1
1Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
Bioconjugate Chemistry
|December 6, 2023
Summary
Researchers developed a novel antibody-drug conjugate (ADC) linker cleavable by alpha-L-iduronidase (IduA), an enzyme overexpressed in tumors but not healthy cells. This new linker shows promise for improved ADC safety and efficacy.
Area of Science:
- Bioconjugation Chemistry
- Antibody-Drug Conjugate (ADC) Development
- Enzyme-Mediated Drug Delivery
Background:
- Antibody-drug conjugates (ADCs) rely on linkers for therapeutic success, requiring stability in circulation and efficient drug release in target cells.
- Current enzymatically cleavable linkers have limitations, with some causing side effects due to enzyme expression in non-target tissues.
- Alpha-L-iduronidase (IduA) was identified as a promising enzyme for ADC linker cleavage due to its tumor-specific expression profile.
Purpose of the Study:
- To develop and evaluate a novel alpha-L-iduronidase (IduA)-cleavable linker for antibody-drug conjugates (ADCs).
- To assess the efficacy and safety profile of ADCs utilizing the IduA-cleavable linker with exatecan and duocarmycin payloads.
- To compare the performance of the IduA-cleavable linker against established ADC linker technologies.
Main Methods:
- Bioinformatic screening to identify IduA as a target enzyme for ADC linker cleavage.
- Synthesis and in vitro cleavage assays of IduA-cleavable linkers using recombinant IduA and cell lysates.
- Conjugation of iduronide-exatecan and iduronide-duocarmycin payloads to an anti-CEACAM5 antibody via interchain cysteines or microbial transglutaminase (mTG).
- Assessment of ADC serum stability, target-dependent cytotoxicity, and comparison with a cathepsin B-activatable ADC.
Main Results:
- Demonstrated functionality of the novel IduA-cleavable linker system in biochemical and cellular assays.
- Iduronide-exatecan ADC exhibited high serum stability and potent, target-dependent tumor cell killing.
- Compared to a valine-citrulline ADC, the iduronide-exatecan ADC showed reduced toxicity in nonmalignant cells.
- In vivo antitumor activity was confirmed for an IduA-cleavable duocarmycin ADC.
Conclusions:
- The novel IduA-cleavable linker system holds significant potential for advancing ADC development.
- This linker technology offers a strategy to enhance tumor selectivity and improve the safety profile of ADCs.
- Further research into iduronide linkers can contribute to a better balance between therapeutic efficacy and reduced off-target toxicity.
