Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice

Abstract

Current antibody-drug conjugates (ADCs) target internalising receptors on cancer cells leading to intracellular drug release. Typically, only a subset of patients with solid tumours has sufficient expression of such a receptor, while there are suitable non-internalising receptors and stroma targets. Here, we demonstrate potent therapy in murine tumour models using a non-internalising ADC that releases its drugs upon a click reaction with a chemical activator, which is administered in a second step. This was enabled by the development of a diabody-based ADC with a high tumour uptake and very low retention in healthy tissues, allowing systemic administration of the activator 2 days later, leading to efficient and selective activation throughout the tumour. In contrast, the analogous ADC comprising the protease-cleavable linker used in the FDA approved ADC Adcetris is not effective in these tumour models. This first-in-class ADC holds promise for a broader applicability of ADCs across patient populations.

Dissociative Bioorthogonal Reactions

“…Electron density on the tetrazine affects the tautomerization of the intermediates with a decreased electron density inhibiting release. Nevertheless, tetrazines with two alkyl substituents react with carbamate‐modified trans ‐cyclooctenes at a rate of up to 54.7 m −1 s −1 in PBS at 37 °C, which is the fastest reported dissociative iEDDA reaction that also provides high release yields …”

“…Dissociative bioorthogonal reactions can also be combined with antibody–drug conjugates (Scheme B). Researchers have developed antibody–drug conjugates in which drugs were linked to the antibody through a trans ‐cyclooctene linker . Rossin et al.…”

Innovative Linker Strategies for Tumor‐Targeted Drug Conjugates

“…Treatment of tumor‐bearing mice with 4 cycles of the 65 – 66 combination led to remarkable anticancer effects and this activity was significantly higher than the one showed by single‐treatment with an analogous MMAE‐based ADC equipped with the Val‐Cit linker . Following a different approach, Chen, Gao and co‐workers applied the “click and release” protocol with the TCO‐tetrazine pair to the tumor‐targeted enzyme instructed supramolecular self‐assembly (EISA) context .…”

The Emerging Role of Tetrazines in Drug‐Activation Chemistries

“…He successfully showed that tetrazine triggers the release of the cell‐permeable peptide monomethyl auristatin E in mice bearing cancer xenografts. This work demonstrated that TCO‐based prodrug systems offer a new approach for controlled drug release by targeting non‐internalising receptors; although the activation was relatively slow, this could well be beneficial for controlled and longer‐term dosing . Recently, the authors showed that this TCO‐based release mechanism could also be used for masking esters and alcohols, while Pluth reported a thiocarbamate linkage that allowed the release of carbonyl sulfide as a gastrotransmitter .…”