Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F22%3A00569602" target="_blank" >RIV/61388971:_____/22:00569602 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/86652036:_____/22:00569602

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S2211124722013286?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S2211124722013286?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.celrep.2022.111478" target="_blank" >10.1016/j.celrep.2022.111478</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection

Popis výsledku v původním jazyce

Low-dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine's preferential expansion of immunosuppressive regulatory T cells (Tregs). However, off-target immune cell activation and short serum half-life limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating Tregs over immune effector cells. Although promising, therapeutic translation of this approach is complicated by the need to optimize dosing ratios and by the instability of the cytokine/antibody complex. We leverage structural insights to engineer a single-chain hIL-2/F5111 antibody fusion protein, termed F5111 immunocytokine (IC), which potently and selectively activates and expands Tregs. F5111 IC confers protection in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus. These results provide a roadmap for IC design and establish a Treg-biased immunotherapy that could be clinically translated for autoimmune disease treatment.

Název v anglickém jazyce

Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection

Popis výsledku anglicky

Low-dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine's preferential expansion of immunosuppressive regulatory T cells (Tregs). However, off-target immune cell activation and short serum half-life limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating Tregs over immune effector cells. Although promising, therapeutic translation of this approach is complicated by the need to optimize dosing ratios and by the instability of the cytokine/antibody complex. We leverage structural insights to engineer a single-chain hIL-2/F5111 antibody fusion protein, termed F5111 immunocytokine (IC), which potently and selectively activates and expands Tregs. F5111 IC confers protection in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus. These results provide a roadmap for IC design and establish a Treg-biased immunotherapy that could be clinically translated for autoimmune disease treatment.

Druh

J_SC - Článek v periodiku v databázi SCOPUS

CEP obor

—

OECD FORD obor

30102 - Immunology

Projekt

<a href="/cs/project/GA20-13029S" target="_blank" >GA20-13029S: Vývoj klinicky relevantních IL-2 imunoterapeutik pro léčbu nádorů</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Cell Reports

ISSN

2211-1247

e-ISSN

2211-1247

Svazek periodika

41

Číslo periodika v rámci svazku

3

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

32

Strana od-do

111478

Kód UT WoS článku

—

EID výsledku v databázi Scopus

2-s2.0-85140093956