Balancing receptor engagement and payload catalytic activity broadens the therapeutic window of immunotoxins
Immunotoxins (ITs) are potent targeted cancer therapeutics that couple tumor-selective receptor binding with efficient intracellular delivery and cytotoxic enzymatic activity of bacterial toxins. While ITs have shown impressive efficacy in hematologic malignancies, dose-limiting toxicity remains a major barrier to their broader clinical application, particularly in solid tumors. The exceptional…
Immunotoxins, a powerful type of targeted cancer therapy, combine the ability to bind to specific tumor receptors with the delivery of enzymatic activity from bacterial toxins. Despite their promise in treating hematological cancers, immunotoxins face the challenge of dose-limiting toxicity, particularly when dealing with solid tumors. This toxicity arises because even a minimal uptake of receptor-low cells by the potent payload can trigger cell death.
In a recent study, researchers delved into the relationship between receptor-binding domain (RBD) affinity and avidity, and the catalytic activity of the payload, to understand how these factors influence the selectivity of immunotoxins. Using immunotoxins targeting CD123, HER3, and HER2 receptors, they discovered that increasing RBD affinity or avidity impacted potency but did not offer precise control over the selectivity between receptor-high and receptor-low cells.
However, reducing the payload's catalytic activity led to significant improvements in selectivity when the payload potency was perfectly matched to the receptor engagement.
The ideal level of payload attenuation varied depending on the receptor context and the type of toxin scaffold employed, demonstrating that the key to achieving maximal selectivity lies in striking a balance between cellular delivery and catalytic activity, rather than simply optimizing one property over the other. In practical applications, attenuating the payload resulted in a remarkable 400-fold increase in the maximum tolerated dose of a HER2-targeted immunotoxin.
Importantly, this modified version maintained robust antitumor activity well below its toxicity threshold, while the unmodified counterpart showed no detectable efficacy at similar doses. These findings not only elucidate the crucial role of payload activity in determining immunotoxin selectivity, but also offer a framework for tailoring receptor engagement with catalytic potency to develop safer and more broadly applicable targeted therapies.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
