Zhou, Xueyuan ; Geyer, Felix Klaus ; Happel, Dominic ; Takimoto, Jeffrey ; Kolmar, Harald ; Rabinovich, Brian (2024)
Using protein geometry to optimize cytotoxicity and the cytokine window of a ROR1 specific T cell engager.
In: Frontiers in Immunology, 15
doi: 10.3389/fimmu.2024.1323049
Artikel, Bibliographie
Dies ist die neueste Version dieses Eintrags.
Kurzbeschreibung (Abstract)
T cell engaging bispecific antibodies have shown clinical proof of concept for hematologic malignancies. Still, cytokine release syndrome, neurotoxicity, and on-target-off-tumor toxicity, especially in the solid tumor setting, represent major obstacles. Second generation TCEs have been described that decouple cytotoxicity from cytokine release by reducing the apparent binding affinity for CD3 and/or the TAA but the results of such engineering have generally led only to reduced maximum induction of cytokine release and often at the expense of maximum cytotoxicity. Using ROR1 as our model TAA and highly modular camelid nanobodies, we describe the engineering of a next generation decoupled TCE that incorporates a “cytokine window” defined as a dose range in which maximal killing is reached but cytokine release may be modulated from very low for safety to nearly that induced by first generation TCEs. This latter attribute supports pro-inflammatory anti-tumor activity including bystander killing and can potentially be used by clinicians to safely titrate patient dose to that which mediates maximum efficacy that is postulated as greater than that possible using standard second generation approaches. We used a combined method of optimizing TCE mediated synaptic distance and apparent affinity tuning of the TAA binding arms to generate a relatively long but persistent synapse that supports a wide cytokine window, potent killing and a reduced propensity towards immune exhaustion. Importantly, this next generation TCE induced significant tumor growth inhibition in vivo but unlike a first-generation non-decoupled benchmark TCE that induced lethal CRS, no signs of adverse events were observed.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2024 |
| Autor(en): | Zhou, Xueyuan ; Geyer, Felix Klaus ; Happel, Dominic ; Takimoto, Jeffrey ; Kolmar, Harald ; Rabinovich, Brian |
| Art des Eintrags: | Bibliographie |
| Titel: | Using protein geometry to optimize cytotoxicity and the cytokine window of a ROR1 specific T cell engager |
| Sprache: | Englisch |
| Publikationsjahr: | 22 Februar 2024 |
| Ort: | Lausanne |
| Verlag: | Frontiers Media S.A. |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Frontiers in Immunology |
| Jahrgang/Volume einer Zeitschrift: | 15 |
| Kollation: | 16 Seiten |
| DOI: | 10.3389/fimmu.2024.1323049 |
| Zugehörige Links: | |
| Kurzbeschreibung (Abstract): | T cell engaging bispecific antibodies have shown clinical proof of concept for hematologic malignancies. Still, cytokine release syndrome, neurotoxicity, and on-target-off-tumor toxicity, especially in the solid tumor setting, represent major obstacles. Second generation TCEs have been described that decouple cytotoxicity from cytokine release by reducing the apparent binding affinity for CD3 and/or the TAA but the results of such engineering have generally led only to reduced maximum induction of cytokine release and often at the expense of maximum cytotoxicity. Using ROR1 as our model TAA and highly modular camelid nanobodies, we describe the engineering of a next generation decoupled TCE that incorporates a “cytokine window” defined as a dose range in which maximal killing is reached but cytokine release may be modulated from very low for safety to nearly that induced by first generation TCEs. This latter attribute supports pro-inflammatory anti-tumor activity including bystander killing and can potentially be used by clinicians to safely titrate patient dose to that which mediates maximum efficacy that is postulated as greater than that possible using standard second generation approaches. We used a combined method of optimizing TCE mediated synaptic distance and apparent affinity tuning of the TAA binding arms to generate a relatively long but persistent synapse that supports a wide cytokine window, potent killing and a reduced propensity towards immune exhaustion. Importantly, this next generation TCE induced significant tumor growth inhibition in vivo but unlike a first-generation non-decoupled benchmark TCE that induced lethal CRS, no signs of adverse events were observed. |
| Freie Schlagworte: | T cell engager, cytokine release syndrome, ROR1, decoupling of cytotoxicity, VHH |
| ID-Nummer: | Artikel-ID: 1323049 |
| Zusätzliche Informationen: | Sec. Cancer Immunity and Immunotherapy |
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 540 Chemie 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin, Gesundheit |
| Fachbereich(e)/-gebiet(e): | Interdisziplinäre Forschungsprojekte Interdisziplinäre Forschungsprojekte > Centre for Synthetic Biology 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut |
| Hinterlegungsdatum: | 05 Jun 2024 09:39 |
| Letzte Änderung: | 05 Jun 2024 12:14 |
| PPN: | 518841782 |
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| Suche nach Titel in: | TUfind oder in Google |
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Using protein geometry to optimize cytotoxicity and the cytokine window of a ROR1 specific T cell engager. (deposited 04 Jun 2024 12:47)
- Using protein geometry to optimize cytotoxicity and the cytokine window of a ROR1 specific T cell engager. (deposited 05 Jun 2024 09:39) [Gegenwärtig angezeigt]
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