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 therapeutic...
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Autor*in:	Adrian Valentin Dinh-Fricke [verfasserIn] Oliver Hantschel [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Schlagwörter:	monobody targeted therapies pharmacokinetics albumin binding domain protein engineering protein therapeutics

Übergeordnetes Werk:	In: Frontiers in Pharmacology - Frontiers Media S.A., 2010, 15(2024)
Übergeordnetes Werk:	volume:15 ; year:2024

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fphar.2024.1393112

Katalog-ID:	DOAJ09869748X

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callnumber-first	R - Medicine
author	Adrian Valentin Dinh-Fricke
spellingShingle	Adrian Valentin Dinh-Fricke misc RM1-950 misc monobody misc targeted therapies misc pharmacokinetics misc albumin binding domain misc protein engineering misc protein therapeutics misc Therapeutics. Pharmacology Improving the pharmacokinetics, biodistribution and plasma stability of monobodies
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topic_title	RM1-950 Improving the pharmacokinetics, biodistribution and plasma stability of monobodies monobody targeted therapies pharmacokinetics albumin binding domain protein engineering protein therapeutics
topic	misc RM1-950 misc monobody misc targeted therapies misc pharmacokinetics misc albumin binding domain misc protein engineering misc protein therapeutics misc Therapeutics. Pharmacology
topic_unstemmed	misc RM1-950 misc monobody misc targeted therapies misc pharmacokinetics misc albumin binding domain misc protein engineering misc protein therapeutics misc Therapeutics. Pharmacology
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title	Improving the pharmacokinetics, biodistribution and plasma stability of monobodies
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title_full	Improving the pharmacokinetics, biodistribution and plasma stability of monobodies
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title_sort	improving the pharmacokinetics, biodistribution and plasma stability of monobodies
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title_auth	Improving the pharmacokinetics, biodistribution and plasma stability of monobodies
abstract	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.
abstractGer	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.
abstract_unstemmed	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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title_short	Improving the pharmacokinetics, biodistribution and plasma stability of monobodies
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