Jäger, Sebastian ; Dickgiesser, Stephan ; Tonillo, Jason ; Hecht, Stefan ; Kolmar, Harald ; Schröter, Christian (2024)
EGFR binding Fc domain-drug conjugates: stable and highly potent cytotoxic molecules mediate selective cell killing.
In: Biological Chemistry, 2022, 403 (5-6)
doi: 10.26083/tuprints-00027284
Artikel, Zweitveröffentlichung, Verlagsversion
 | Es ist eine neuere Version dieses Eintrags verfügbar. |
Kurzbeschreibung (Abstract)
The exposition of cancer cells to cytotoxic doses of payload is fundamental for the therapeutic efficacy of antibody drug conjugates (ADCs) in solid cancers. To maximize payload exposure, tissue penetration can be increased by utilizing smaller-sized drug conjugates which distribute deeper into the tumor. Our group recently explored small human epidermal growth factor receptor 2 (HER2) targeting Fc antigen binding fragments (Fcabs) for ADC applications in a feasibility study. Here, we expand this concept using epidermal growth factor receptor (EGFR) targeting Fcabs for the generation of site-specific auristatin-based drug conjugates. In contrast to HER2-targeting Fcabs, we identified novel conjugation sites in the EGFR-targeting Fcab scaffold that allowed for higher DAR enzymatic conjugation. We demonstrate feasibility of resultant EGFR-targeting Fcab-drug conjugates that retain binding to half-life prolonging neonatal Fc receptor (FcRn) and EGFR and show high serum stability as well as target receptor mediated cell killing at sub-nanomolar concentrations. Our results emphasize the applicability of the Fcab format for the generation of drug conjugates designed for increased penetration of solid tumors and potential FcRn-driven antibody-like pharmacokinetics.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2024 |
| Autor(en): | Jäger, Sebastian ; Dickgiesser, Stephan ; Tonillo, Jason ; Hecht, Stefan ; Kolmar, Harald ; Schröter, Christian |
| Art des Eintrags: | Zweitveröffentlichung |
| Titel: | EGFR binding Fc domain-drug conjugates: stable and highly potent cytotoxic molecules mediate selective cell killing |
| Sprache: | Englisch |
| Publikationsjahr: | 29 April 2024 |
| Ort: | Darmstadt |
| Publikationsdatum der Erstveröffentlichung: | 2022 |
| Ort der Erstveröffentlichung: | Berlin [u.a] |
| Verlag: | De Gruyter |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Biological Chemistry |
| Jahrgang/Volume einer Zeitschrift: | 403 |
| (Heft-)Nummer: | 5-6 |
| DOI: | 10.26083/tuprints-00027284 |
| URL / URN: | https://tuprints.ulb.tu-darmstadt.de/27284 |
| Zugehörige Links: | |
| Herkunft: | Zweitveröffentlichungsservice |
| Kurzbeschreibung (Abstract): | The exposition of cancer cells to cytotoxic doses of payload is fundamental for the therapeutic efficacy of antibody drug conjugates (ADCs) in solid cancers. To maximize payload exposure, tissue penetration can be increased by utilizing smaller-sized drug conjugates which distribute deeper into the tumor. Our group recently explored small human epidermal growth factor receptor 2 (HER2) targeting Fc antigen binding fragments (Fcabs) for ADC applications in a feasibility study. Here, we expand this concept using epidermal growth factor receptor (EGFR) targeting Fcabs for the generation of site-specific auristatin-based drug conjugates. In contrast to HER2-targeting Fcabs, we identified novel conjugation sites in the EGFR-targeting Fcab scaffold that allowed for higher DAR enzymatic conjugation. We demonstrate feasibility of resultant EGFR-targeting Fcab-drug conjugates that retain binding to half-life prolonging neonatal Fc receptor (FcRn) and EGFR and show high serum stability as well as target receptor mediated cell killing at sub-nanomolar concentrations. Our results emphasize the applicability of the Fcab format for the generation of drug conjugates designed for increased penetration of solid tumors and potential FcRn-driven antibody-like pharmacokinetics. |
| Freie Schlagworte: | antibody-drug conjugates, antibody engineering, drug delivery, Fc antigen binding fragments, transglutaminase, tumor penetration |
| Status: | Verlagsversion |
| URN: | urn:nbn:de:tuda-tuprints-272847 |
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 540 Chemie |
| Fachbereich(e)/-gebiet(e): | 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut |
| Hinterlegungsdatum: | 29 Apr 2024 13:50 |
| Letzte Änderung: | 30 Apr 2024 05:47 |
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| Suche nach Titel in: | TUfind oder in Google |
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- EGFR binding Fc domain-drug conjugates: stable and highly potent cytotoxic molecules mediate selective cell killing. (deposited 29 Apr 2024 13:50) [Gegenwärtig angezeigt]
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