دورية أكاديمية
A Bispecific Monoclonal Antibody Targeting Psl and PcrV Enhances Neutrophil-Mediated Killing of Pseudomonas aeruginosa in Patients with Bronchiectasis.
| العنوان: | A Bispecific Monoclonal Antibody Targeting Psl and PcrV Enhances Neutrophil-Mediated Killing of Pseudomonas aeruginosa in Patients with Bronchiectasis. |
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| المؤلفون: | Long MB; Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom., Gilmour A; Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom., Kehl M; Vaccine and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland., Tabor DE; Vaccine and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland., Keller AE; Vaccine and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland., Warrener P; Vaccine and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland., Gopalakrishnan V; Vaccine and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland., Rosengren S; Translational Science and Experimental Medicine, Respiratory & Immunology, Respiratory and Immunology, and., Crichton ML; Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom., McIntosh E; Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom., Giam YH; Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom., Keir HR; Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom., Brailsford W; Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; and., Hughes R; Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Belvisi MG; Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; and., Sellman BR; Vaccine and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland., DiGiandomenico A; Vaccine and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland., Chalmers JD; Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom. |
| المصدر: | American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2024 Jul 01; Vol. 210 (1), pp. 35-46. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Thoracic Society Country of Publication: United States NLM ID: 9421642 Publication Model: Print Cited Medium: Internet ISSN: 1535-4970 (Electronic) Linking ISSN: 1073449X NLM ISO Abbreviation: Am J Respir Crit Care Med Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2000- : New York, NY : American Thoracic Society Original Publication: New York, NY : American Lung Association, c1994- |
| مواضيع طبية MeSH: | Bronchiectasis*/immunology , Bronchiectasis*/microbiology , Pseudomonas aeruginosa*/immunology , Neutrophils*/immunology , Neutrophils*/drug effects , Antibodies, Bispecific*/therapeutic use , Antibodies, Bispecific*/pharmacology , Pseudomonas Infections*/immunology, Humans ; Female ; Male ; Middle Aged ; Aged ; Adult ; Antigens, Bacterial ; Bacterial Toxins ; Pore Forming Cytotoxic Proteins |
| مستخلص: | 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. |
| التعليقات: | Comment in: Am J Respir Crit Care Med. 2024 Jul 1;210(1):8-9. doi: 10.1164/rccm.202405-0974ED. (PMID: 38780075) |
| معلومات مُعتمدة: | AstraZeneca; European Respiratory Society |
| فهرسة مساهمة: | Keywords: antibody; bronchiectasis; infection; neutrophil |
| المشرفين على المادة: | 0 (Antibodies, Bispecific) 0 (antigen V, Pseudomonas) 0 (Antigens, Bacterial) 0 (Bacterial Toxins) 0 (Pore Forming Cytotoxic Proteins) |
| تواريخ الأحداث: | Date Created: 20240516 Date Completed: 20240701 Latest Revision: 20240801 |
| رمز التحديث: | 20240801 |
| DOI: | 10.1164/rccm.202308-1403OC |
| PMID: | 38754132 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1535-4970 |
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| DOI: | 10.1164/rccm.202308-1403OC |