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Improving the pharmacokinetics, biodistribution and plasma stability of monobodies
Cancer is a leading cause of death worldwide. Several targeted anticancer drugs entered clinical practice and improved survival of cancer patients with selected tumor types, but therapy resistance and metastatic disease remains a challenge. A major class of targeted anticancer drugs are therapeut...
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| Autoren: | , |
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| Format: | Artikel |
| Sprache: | Englisch |
| Veröffentlicht: |
Philipps-Universität Marburg
2024
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| Online-Zugang: | PDF-Volltext |
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| Zusammenfassung: | Cancer is a leading cause of death worldwide. Several targeted anticancer drugs
entered clinical practice and improved survival of cancer patients with selected
tumor types, but therapy resistance and metastatic disease remains a challenge. A
major class of targeted anticancer drugs are therapeutic antibodies, but their use
is limited to extracellular targets. Hence, alternative binding scaffolds have been
investigated for intracellular use and better tumor tissue penetration. Among
those, monobodies are small synthetic protein binders that were engineered to
bind with high affinity and selectivity to central intracellular oncoproteins and
inhibit their signaling. Despite their use as basic research tools, the potential of
monobodies as protein therapeutics remains to be explored. In particular, the
pharmacological properties of monobodies, including plasma stability, toxicity
and pharmacokinetics have not been investigated. Here, we show that
monobodies have high plasma stability, are well-tolerated in mice, but have a
short half-life in vivo due to rapid renal clearance. Therefore, we engineered
monobody fusions with an albumin-binding domain (ABD), which showed
enhanced pharmacological properties without affecting their target binding:
We found that ABD-monobody fusions display increased stability in mouse
plasma. Most importantly, ABD-monobodies have a dramatically prolonged in
vivo half-life and are not rapidly excreted by renal clearance, remaining in the
blood significantly longer, while not accumulating in specific internal organs. Our
results demonstrate the promise and versatility of monobodies to be developed
into future therapeutics for cancer treatment. We anticipate that monobodies
may be able to extend the spectrum of intracellular targets, resulting in a
significant benefit to patient outcome. |
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| Beschreibung: | Gefördert durch den Open-Access-Publikationsfonds der UB Marburg. |
| DOI: | 10.3389/fphar.2024.1393112 |