Novel humanized anti-PcrV monoclonal antibody COT-143 protects mice from lethal Pseudomonas aeruginosa infection via inhibition of toxin translocation by the type III secretion system.

Autor:	Numata S; Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Toyonaka, Japan., Hara T; Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Toyonaka, Japan., Izawa M; Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Toyonaka, Japan., Okuno Y; Shionogi TechnoAdvance Research & Co., Ltd., Toyonaka, Japan., Sato Y; Business Development Department, Shionogi & Co., Ltd., Toyonaka, Japan., Yamane S; Shionogi TechnoAdvance Research & Co., Ltd., Toyonaka, Japan., Maki H; Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Toyonaka, Japan., Sato T; Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Toyonaka, Japan., Yamano Y; Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Toyonaka, Japan.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Oct 08; Vol. 68 (10), pp. e0069424. Date of Electronic Publication: 2024 Sep 13.
DOI:	10.1128/aac.00694-24
Abstrakt:	Treatment of Pseudomonas aeruginosa infection is challenging due to its intrinsic and acquired antibiotic resistance. As the number of current therapeutic options for P. aeruginosa infections is limited, developing novel treatments against the pathogen is an urgent clinical priority. The suppression of virulence of P. aeruginosa could be a new therapeutic option, and the type III secretion system (T3SS), which enables the bacteria to translocate various kinds of toxins into host cells and inhibits cellular functions, is considered as one possible target. In this report, we examined T3SS inhibition by COT-143/INFEX702, a humanized monoclonal antibody against PcrV, T3SS component, and present the crystal structure of the antibody-PcrV complex. COT-143 inhibited T3SS-dependent cytotoxicity and protected mice from the mortality caused by P. aeruginosa infection. The inhibition of cytotoxicity coincided with inhibition of translocon formation in a host cell membrane, which is necessary for T3SS intoxication. COT-143 protected murine neutrophils and facilitated phagocytosis of P. aeruginosa . These results suggest that COT-143 facilitates P. aeruginosa clearance by protecting neutrophil via inhibition of T3SS-dependent toxin translocation. This is the first report to show that an anti-PcrV antibody directly interferes with translocon formation to inhibit intoxication of host cells. Competing Interests: S.N., T.H., M.I., Y.S., H.M., T.S., and Y.Y. are employees of Shionogi & Co., Ltd. Y.O. and S.Y. are employees of Shionogi TechnoAdvance Research & Co., Ltd., a wholly owned subsidiary of Shionogi & Co., Ltd.
Databáze:	MEDLINE
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