Secretion and surface display of binders of IL-23/IL-17 cytokines and their receptors in<i> Lactococcus</i><i> lactis</i> as a therapeutic approach against inflammation

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F23%3A00576609" target="_blank" >RIV/86652036:_____/23:00576609 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0928098723001987?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0928098723001987?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejps.2023.106568" target="_blank" >10.1016/j.ejps.2023.106568</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Secretion and surface display of binders of IL-23/IL-17 cytokines and their receptors in<i> Lactococcus</i><i> lactis</i> as a therapeutic approach against inflammation

Popis výsledku v původním jazyce

The cytokine IL-23 activates the IL-23 receptor (IL-23R) and stimulates the differentiation of naive T helper (Th) cells into a Th17 cell population that secretes inflammatory cytokines and chemokines. This IL-23/Th17 proinflammatory axis drives inflammation in Crohn's disease and ulcerative colitis and represents a therapeutic target of monoclonal antibodies. Non-immunoglobulin binding proteins based on the Streptococcus albuminbinding domain (ABD) provide a small protein alternative to monoclonal antibodies. They can be readily expressed in bacteria. Lactococcus lactis is a safe lactic acid bacterium that has previously been engineered as a vector for the delivery of recombinant therapeutic proteins to mucosal surfaces. Here, L. lactis was engineered to display or secrete ABD-variants against the IL-17 receptor (IL-17R). Its expression and functionality were confirmed with flow cytometry using specific antibody and recombinant IL-17R, respectively. In addition, L. lactis were engineered into multifunctional bacteria that simultaneously express two binders from pNBBX plasmid. First, binders of IL-17R were combined with binder of IL-17. Second, binders of IL-23R were combined with binders of IL-23. The dual functionality of the bacteria was confirmed by flow cytometry using corresponding targets, namely the recombinant receptors IL-17R and IL-23R or the p19 subunit of IL-23. Binding of IL17 was confirmed by ELISA. With the latter, 97% of IL-17 was removed from solution by 2 x 109 recombinant bacteria. Moreover, multifunctional bacteria targeting IL-17/IL-17R prevented IL-17A-mediated activation of downstream signaling pathways in HEK-Blue IL-17 cell model. Thus, we have developed several multifunctional L. lactis capable of targeting multiple factors of the IL-23/Th17 proinflammatory axis. This represents a novel therapeutic strategy with synergistic potential for the treatment of intestinal inflammations.

Název v anglickém jazyce

Secretion and surface display of binders of IL-23/IL-17 cytokines and their receptors in<i> Lactococcus</i><i> lactis</i> as a therapeutic approach against inflammation

Popis výsledku anglicky

The cytokine IL-23 activates the IL-23 receptor (IL-23R) and stimulates the differentiation of naive T helper (Th) cells into a Th17 cell population that secretes inflammatory cytokines and chemokines. This IL-23/Th17 proinflammatory axis drives inflammation in Crohn's disease and ulcerative colitis and represents a therapeutic target of monoclonal antibodies. Non-immunoglobulin binding proteins based on the Streptococcus albuminbinding domain (ABD) provide a small protein alternative to monoclonal antibodies. They can be readily expressed in bacteria. Lactococcus lactis is a safe lactic acid bacterium that has previously been engineered as a vector for the delivery of recombinant therapeutic proteins to mucosal surfaces. Here, L. lactis was engineered to display or secrete ABD-variants against the IL-17 receptor (IL-17R). Its expression and functionality were confirmed with flow cytometry using specific antibody and recombinant IL-17R, respectively. In addition, L. lactis were engineered into multifunctional bacteria that simultaneously express two binders from pNBBX plasmid. First, binders of IL-17R were combined with binder of IL-17. Second, binders of IL-23R were combined with binders of IL-23. The dual functionality of the bacteria was confirmed by flow cytometry using corresponding targets, namely the recombinant receptors IL-17R and IL-23R or the p19 subunit of IL-23. Binding of IL17 was confirmed by ELISA. With the latter, 97% of IL-17 was removed from solution by 2 x 109 recombinant bacteria. Moreover, multifunctional bacteria targeting IL-17/IL-17R prevented IL-17A-mediated activation of downstream signaling pathways in HEK-Blue IL-17 cell model. Thus, we have developed several multifunctional L. lactis capable of targeting multiple factors of the IL-23/Th17 proinflammatory axis. This represents a novel therapeutic strategy with synergistic potential for the treatment of intestinal inflammations.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/GF21-16423K" target="_blank" >GF21-16423K: Malé proteiny blokující dráhu IL-23/IL-17 jako inhibitory střevního zánětu sekretované probiotickými bakteriemi.</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

European Journal of Pharmaceutical Sciences

ISSN

0928-0987

e-ISSN

1879-0720

Svazek periodika

190

Číslo periodika v rámci svazku

NOV 1 2023

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

10

Strana od-do

106568

Kód UT WoS článku

001070815000001

EID výsledku v databázi Scopus

—