Delving into the Latest Updates on Gremubamab with Synapse

Overview

Basic Info

Drug Type

Bispecific antibody

Synonyms

Anti-Psl/PcrV, BiS4alphaPa

+ [1]

Target

PcrV x PslG

Mechanism

PcrV inhibitors(Pseudomonas aeruginosa PvrV protein inhibitors), PslG inhibitors

Therapeutic Areas

Infectious Diseases

Active Indication

Pseudomonas aeruginosa infection

Inactive Indication

Healthcare-Associated Pneumonia

Originator Organization

MedImmune LLC

Active Organization

MedImmune LLC

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

Sequence Code 157713

Source: *****

Sequence Code 157708

Source: *****

Pseudomonas aeruginosa poses a significant threat to immunocompromised individuals and those with cystic fibrosis. Treatment relies on antibiotics, but persistent infections occur due to intrinsic and acquired resistance of P. aeruginosa towards multiple classes of antibiotics. To date, there are no licensed vaccines for this pathogen, prompting the urgent need for novel treatment approaches to combat P. aeruginosa infection and persistence. Here we validated AAV vectored immunoprophylaxis as a strategy to generate long-term plasma and mucosal expression of highly protective monoclonal antibodies (mAbs) targeting the exopolysaccharide Psl (Cam-003) and the PcrV (V2L2MD) component of the type-III secretion system injectosome either as single mAbs or together as a bispecific mAb (MEDI3902) in a mouse model. When administered intramuscularly, AAV-αPcrV, AAV-αPsl, and AAV-MEDI3902 significantly protected mice challenged intranasally with a lethal dose of P. aeruginosa strains PAO1 and PA14 and reduced bacterial burden and dissemination to other organs. While all AAV-mAbs provided protection, AAV-αPcrV and AAV-MEDI3902 provided 100% and 87.5% protection from a lethal challenge with 4.47 × 10⁷ CFU PAO1 and 87.5% and 75% protection from a lethal challenge with 3 × 10⁷ CFU PA14, respectively. Serum concentrations of MEDI3902 were ~10× lower than that of αPcrV, but mice treated with this vector showed a greater reduction in bacterial dissemination to the liver, lung, spleen, and blood compared to other AAV-mAbs. These results support further investigation into the use of AAV vectored immunoprophylaxis to prevent and treat P. aeruginosa infections and other bacterial pathogens of public health concern for which current treatment strategies are limited.

01 Jul 2024·American Journal of Respiratory and Critical Care Medicine

A Bispecific Monoclonal Antibody Targeting Psl and PcrV Enhances Neutrophil-Mediated Killing of Pseudomonas aeruginosa in Patients with Bronchiectasis

Article

Author: Kehl, Margaret ; Crichton, Megan L. ; Sellman, Bret R. ; Belvisi, Maria G. ; Gilmour, Amy ; Long, Merete B. ; Warrener, Paul ; Hughes, Rod ; Keller, Ashley E. ; DiGiandomenico, Antonio ; McIntosh, Eve ; Keir, Holly R. ; Rosengren, Sanna ; Giam, Yan Hui ; Brailsford, Wayne ; Gopalakrishnan, Vancheswaran ; Tabor, David E. ; Chalmers, James D.

Rationale: Pseudomonas aeruginosa infection is associated with worse outcomes in bronchiectasis. Impaired neutrophil antimicrobial responses contribute to bacterial persistence. Gremubamab is a bivalent, bispecific monoclonal antibody targeting Psl exopolysaccharide and the type 3 secretion system component PcrV. Objectives: This study evaluated the efficacy of gremubamab to enhance killing of P. aeruginosa by neutrophils from patients with bronchiectasis and to prevent P. aeruginosa-associated cytotoxicity. Methods: P. aeruginosa isolates from a global bronchiectasis cohort (n = 100) underwent whole-genome sequencing to determine target prevalence. Functional activity of gremubamab against selected isolates was tested in vitro and in vivo. Patients with bronchiectasis (n = 11) and control subjects (n = 10) were enrolled, and the effect of gremubamab in peripheral blood neutrophil opsonophagocytic killing (OPK) assays against P. aeruginosa was evaluated. Serum antibody titers to Psl and PcrV were determined (n = 30; 19 chronic P. aeruginosa infection, 11 no known P. aeruginosa infection), as was the effect of gremubamab treatment in OPK and anti-cytotoxic activity assays. Measurements and Main Results: Psl and PcrV were conserved in isolates from chronically infected patients with bronchiectasis. Seventy-three of 100 isolates had a full psl locus, and 99 of 100 contained the pcrV gene, with 20 distinct full-length PcrV protein subtypes identified. PcrV subtypes were successfully bound by gremubamab and the monoclonal antibody-mediated potent protective activity against tested isolates. Gremubamab increased bronchiectasis patient neutrophil-mediated OPK (+34.6 ± 8.1%) and phagocytosis (+70.0 ± 48.8%), similar to effects observed in neutrophils from control subjects (OPK, +30.1 ± 7.6%). No evidence of competition between gremubamab and endogenous antibodies was found, with protection against P. aeruginosa-induced cytotoxicity and enhanced OPK demonstrated with and without addition of patient serum. Conclusions: Gremubamab enhanced bronchiectasis patient neutrophil phagocytosis and killing of P. aeruginosa and reduced virulence.

15 Feb 2022·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Antivirulence Bispecific Monoclonal Antibody-Mediated Protection against Pseudomonas aeruginosa Ventilator-Associated Pneumonia in a Rabbit Model

Q2 · MEDICINE

Article

Author: Dong, Oliver X. ; Tran, Vuvi G. ; Stover, Charles K. ; Cheng, Lily I. ; Yu, Li ; Diep, Binh An ; Le, Hoan N. ; DiGiandomenico, Antonio ; Vu, Trang T. T. ; Aguiar-Alves, Fábio ; Sellman, Bret R. ; Quetz, Josiane Silva ; Gras, Emmanuelle

Ventilator-associated pneumonia is an important clinical manifestation of the nosocomial pathogen Pseudomonas aeruginosa . We characterized the correlates of protection with MEDI3902, a bispecific human IgG1 monoclonal antibody that targets the P. aeruginosa type 3 secretion system PcrV protein and the Psl exopolysaccharide, in a rabbit model of ventilator-associated pneumonia using lung-protective, low-tidal-volume mechanical ventilation.

100 Deals associated with Gremubamab

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15014

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pseudomonas Infections	Discovery	BE	MedImmune LLC	25 Mar 2016
Pseudomonas Infections	Discovery	AT	MedImmune LLC	25 Mar 2016
Pseudomonas Infections	Discovery	CZ	MedImmune LLC	25 Mar 2016
Pseudomonas Infections	Discovery	PT	MedImmune LLC	25 Mar 2016
Pseudomonas Infections	Discovery	US	MedImmune LLC	25 Mar 2016
Pseudomonas Infections	Discovery	HR	MedImmune LLC	25 Mar 2016
Pseudomonas Infections	Discovery	GB	MedImmune LLC	25 Mar 2016
Pseudomonas Infections	Discovery	FR	MedImmune LLC	25 Mar 2016
Pseudomonas Infections	Discovery	GR	MedImmune LLC	25 Mar 2016
Pseudomonas Infections	Discovery	IE	MedImmune LLC	25 Mar 2016

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02696902 (EVADE, CTgov)	Phase 2	Pseudomonas Infections \| Healthcare-Associated Pneumonia	188	Placebo (Placebo)	hwxidmeyvh(yxmdwgkzmk) = uojlwpjmwz ytbohkkncp (jwcrqlxnht, ygyqkjoeit - bjbzfjsssl) View more	-	23 Dec 2020
				MEDI3902 (MEDI3902 500 mg)	hwxidmeyvh(yxmdwgkzmk) = ngqjstnott ytbohkkncp (jwcrqlxnht, ayzohuqkoo - koyfzeqnsd) View more
NCT02255760 (CTgov)	Phase 1	Pseudomonas Infections	56	Placebo (Placebo)	nznxmfsyfy(bhkaansomy) = ckfxkuetmz mosxjbmavh (lchnrzihtn, ngzawnzsly - urynavgyjs) View more	-	13 Aug 2018
				MEDI3902 - Dose 1 (MEDI3902 - Dose 1)	nznxmfsyfy(bhkaansomy) = anhaihsozl mosxjbmavh (lchnrzihtn, wuefvrocrb - qhmpsnuial) View more