A multifunctional bispecific antibody protects against Pseudomonas aeruginosa.
Widespread drug resistance due to empiric use of broad-spectrum antibiotics has stimulated development of bacteria-specific strategies for prophylaxis and therapy based on modern monoclonal antibody (mAb) technologies. However, single-mechanism mAb approaches have not provided adequate protective activity in the clinic. We constructed multifunctional bispecific antibodies, each conferring three mechanisms of action against the bacterial pathogen Pseudomonas aeruginosa by targeting the serotype-independent type III secretion system (injectisome) virulence factor PcrV and persistence factor Psl exopolysaccharide. A new bispecific antibody platform, BiS4, exhibited superior synergistic protection against P. aeruginosa-induced murine pneumonia compared to parent mAb combinations or other available bispecific antibody structures. BiS4αPa was protective in several mouse infection models against disparate P. aeruginosa strains and unexpectedly further synergized with multiple antibiotic classes even against drug-resistant clinical isolates. In addition to resulting in a multimechanistic clinical candidate (MEDI3902) for the prevention or treatment of P. aeruginosa infections, these antibody studies suggest that multifunctional antibody approaches may be a promising platform for targeting other antibiotic-resistant bacterial pathogens.
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Antonio
A
DiGiandomenico
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Ashley E
AE
Keller
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Cuihua
C
Gao
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Godfrey J
GJ
Rainey
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Paul
P
Warrener
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Mareia M
MM
Camara
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Jessica
J
Bonnell
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Ryan
R
Fleming
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Binyam
B
Bezabeh
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Nazzareno
N
Dimasi
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Bret R
BR
Sellman
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Jamese
J
Hilliard
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Caitlin M
CM
Guenther
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Vivekananda
V
Datta
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Wei
W
Zhao
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Changshou
C
Gao
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
Xiang-Qing
XQ
Yu
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA.
JoAnn A
JA
Suzich
MedImmune, LLC, One MedImmune Way, Gaithersburg, MD 20878, USA. stoverk@medimmune.com.
C Kendall
CK
Stover
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000907:Antibodies, Bacterial / Q000737:chemistry / Q000627:therapeutic use*; D018033:Antibodies, Bispecific / Q000737:chemistry / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D000942:Antigens, Bacterial / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D010587:Phagocytosis; D011552:Pseudomonas Infections / Q000276:immunology / Q000628:therapy*; D011550:Pseudomonas aeruginosa / Q000276:immunology*
D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial