Development of a Bispecific Antibody Targeting Clinical Isolates of Acinetobacter baumannii.
Acinetobacter baumannii
bispecific monoclonal antibody
carbapenem resistant
extreme drug resistance
immunotherapy
Journal
The Journal of infectious diseases
ISSN: 1537-6613
Titre abrégé: J Infect Dis
Pays: United States
ID NLM: 0413675
Informations de publication
Date de publication:
26 04 2023
26 04 2023
Historique:
received:
13
07
2022
accepted:
05
01
2023
pmc-release:
06
01
2024
medline:
28
4
2023
pubmed:
9
1
2023
entrez:
8
1
2023
Statut:
ppublish
Résumé
We previously reported developing 2 anticapsular monoclonal antibodies (mAbs) as a novel therapy for Acinetobacter baumannii infections. We sought to determine whether a bispecific mAb (bsAb) could improve avidity and efficacy while maximizing strain coverage in one molecule. Humanized mAb 65 was cloned into a single-chain variable fragment and attached to humanized mAb C8, combining their paratopes into a single bsAb (C73). We tested bsAb C73's strain coverage, binding affinity, ex vivo opsonic activity, and in vivo efficacy compared to each mAb alone and combined. The bsAb demonstrated strain coverage, binding affinity, opsonization, and in vivo efficacy superior to either original mAb alone or combined. A humanized bsAb targeting distinct A. baumannii capsule moieties enabled potent and effective coverage of disparate A. baumannii clinical isolates. The bsAb enhances feasibility of development by minimizing the number of components of a promising novel therapeutic for these difficult-to-treat infections.
Sections du résumé
BACKGROUND
We previously reported developing 2 anticapsular monoclonal antibodies (mAbs) as a novel therapy for Acinetobacter baumannii infections. We sought to determine whether a bispecific mAb (bsAb) could improve avidity and efficacy while maximizing strain coverage in one molecule.
METHODS
Humanized mAb 65 was cloned into a single-chain variable fragment and attached to humanized mAb C8, combining their paratopes into a single bsAb (C73). We tested bsAb C73's strain coverage, binding affinity, ex vivo opsonic activity, and in vivo efficacy compared to each mAb alone and combined.
RESULTS
The bsAb demonstrated strain coverage, binding affinity, opsonization, and in vivo efficacy superior to either original mAb alone or combined.
CONCLUSIONS
A humanized bsAb targeting distinct A. baumannii capsule moieties enabled potent and effective coverage of disparate A. baumannii clinical isolates. The bsAb enhances feasibility of development by minimizing the number of components of a promising novel therapeutic for these difficult-to-treat infections.
Identifiants
pubmed: 36617220
pii: 6973037
doi: 10.1093/infdis/jiac499
pmc: PMC10319980
doi:
Substances chimiques
Antibodies, Monoclonal
0
Single-Chain Antibodies
0
Antibodies, Bispecific
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1042-1049Subventions
Organisme : NIAID NIH HHS
ID : R21 AI127954
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI130060
Pays : United States
Organisme : NIAID NIH HHS
ID : P30 AI028697
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI139052
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI117211
Pays : United States
Organisme : NIAID NIH HHS
ID : R42 AI106375
Pays : United States
Organisme : NIAID NIH HHS
ID : R41 AI106375
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Déclaration de conflit d'intérêts
Potential conflicts of interest . T. B. N. and B. S. are inventors on patents related to monoclonal antibodies C8 and 65. T. B. N., J. Y., B. M. L., and B. S. are inventors on a patent related to bispecific monoclonal antibody C73. T. B. N. and B. S. own equity in BioAIM, which is developing the antibodies. U. S. C. has an ownership interest in BioAIM and is entitled to a share of royalties based on a licensing agreement with BioAIM. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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