2022
DOI: 10.1021/acsmedchemlett.2c00394
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Complementation Dependent Enzyme Prodrug Therapy Enables Targeted Activation of Prodrug on HER2-Positive Cancer Cells

Abstract: Antibodies have been explored for decades for the delivery of small molecule cytotoxins directly to diseased cells. In antibody-directed enzyme prodrug therapy (ADEPT), antibodies are armed with enzymes that activate nontoxic prodrugs at tumor sites. However, this strategy failed clinically due to off-target toxicity associated with the enzyme prematurely activating prodrug systemically. We describe here the design of an antibody-fragment split enzyme platform that regains activity after binding to HER2, allow… Show more

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Cited by 9 publications
(7 citation statements)
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“…For example, eRBCs that sense circulating toxins (e.g., botulinum neurotoxin) could act as a theranostic that both sequesters the toxin and reports on its presence. Alternatively, the output of a biosensing eRBC could comprise reconstitution of a split enzyme that converts a coloaded prodrug into an active drug, on-site in the body . Broadly, we envision eRBC products as tools that could provide previously inaccessible information and tools to physicians and patients, helping to reduce morbidity and mortality for a wide range of conditions.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…For example, eRBCs that sense circulating toxins (e.g., botulinum neurotoxin) could act as a theranostic that both sequesters the toxin and reports on its presence. Alternatively, the output of a biosensing eRBC could comprise reconstitution of a split enzyme that converts a coloaded prodrug into an active drug, on-site in the body . Broadly, we envision eRBC products as tools that could provide previously inaccessible information and tools to physicians and patients, helping to reduce morbidity and mortality for a wide range of conditions.…”
Section: Discussionmentioning
confidence: 99%
“…Alternatively, the output of a biosensing eRBC could comprise reconstitution of a split enzyme that converts a coloaded prodrug into an active drug, on-site in the body. 88 Broadly, we envision eRBC products as tools that could provide previously inaccessible information and tools to physicians and patients, helping to reduce morbidity and mortality for a wide range of conditions. The RBC-protein-based biosensors developed in this study comprise a key first step toward realizing this potential.…”
Section: ■ Discussionmentioning
confidence: 99%
“…Thus, C max occurred shortly after insonation, as a guide to set time points in the net-influx phase. The present data can be references for exploring PK in other prodrug–enzyme systems. …”
mentioning
confidence: 88%
“…Expanding upon this concept, Nervieg et al . adapted the split TEM‐1 approach to specifically activate prodrugs with high precision [8a] . The ability of split β‐lactamase to selectively break down β‐lactam‐containing compounds allows for broadened research opportunities through tailored substrate design and genetic circuitry.…”
Section: Scopes Of Split Proteinsmentioning
confidence: 99%
“…In therapeutic contexts, split protein systems have demonstrated significant potential. For example, split β‐lactamase, when fused to binders of cancer biomarkers, can reassemble at target sites, enabling the activation and localized release of drugs by cleaving the β‐lactam group [8a] . The paCas9 system, combining split Cas9 and optogenetics, allows for the targeted destruction of the anti‐apoptotic gene survivin , achieving precise tumor volume reduction [5b] .…”
Section: Applicationsmentioning
confidence: 99%