A novel anti-PcrV antibody providing enhanced protection against Pseudomonas aeruginosa in multiple animal infection models.
Pseudomonas aeruginosa is a major cause of hospital-acquired infections, particularly in mechanically ventilated patients, and it is the leading cause of death in cystic fibrosis patients. A key virulence factor associated with disease severity is the P. aeruginosa type III secretion system (T3SS), which injects bacterial toxins directly into the cytoplasm of host cells. The PcrV protein, located at the tip of the T3SS injectisome complex, is required for T3SS function and is a well-validated target in animal models of immunoprophylactic strategies targeting P. aeruginosa. In an effort to identify a highly potent and protective monoclonal antibody (MAb) that inhibits the T3SS, we generated and characterized a panel of novel anti-PcrV MAbs. Interestingly, some MAbs exhibiting potent inhibition of T3SS in vitro failed to provide protection in a mouse model of P. aeruginosa infection, suggesting that effective in vivo inhibition of T3SS with anti-PcrV MAbs is epitope dependent. V2L2MD, while not the most potent MAb as assessed by in vitro cytotoxicity inhibition assays, provided strong prophylactic protection in several murine infection models and a postinfection therapeutic model. V2L2MD mediated significantly (P < 0.0001) better in vivo protection than that provided by a comparator antibody, MAb166, a well-characterized anti-PcrV MAb and the progenitor of a clinical candidate, KB001-A. The results described here support further development of a V2L2MD-containing immunotherapeutic and may suggest even greater potential than was previously recognized for the prevention and treatment of P. aeruginosa infections in high-risk populations.
Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA.
Paul
P
Warrener
Antibody Discovery and Protein Engineering, MedImmune, LLC, Gaithersburg, Maryland, USA.
Reena
R
Varkey
Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA.
Jessica C
JC
Bonnell
Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA.
Antonio
A
DiGiandomenico
Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA.
Maria
M
Camara
Antibody Discovery and Protein Engineering, MedImmune, LLC, Gaithersburg, Maryland, USA.
Kimberly
K
Cook
Antibody Discovery and Protein Engineering, MedImmune, LLC, Gaithersburg, Maryland, USA.
Li
L
Peng
Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA.
Jingying
J
Zha
Antibody Discovery and Protein Engineering, MedImmune, LLC, Gaithersburg, Maryland, USA.
Partha
P
Chowdury
Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA.
Bret
B
Sellman
Department of Infectious Diseases, MedImmune, LLC, Gaithersburg, Maryland, USA stoverk@medimmune.com.
C Kendall
CK
Stover
D000818:Animals; D000907:Antibodies, Bacterial / Q000008:administration & dosage* / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000096:biosynthesis; D000942:Antigens, Bacterial / Q000737:chemistry / Q000276:immunology*; D058947:Bacterial Secretion Systems / Q000276:immunology; D001427:Bacterial Toxins / Q000737:chemistry / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007116:Immunization, Passive; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D051379:Mice; D052899:Pore Forming Cytotoxic Proteins / Q000737:chemistry / Q000276:immunology*; D011552:Pseudomonas Infections / Q000276:immunology / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology; D016019:Survival Analysis
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D058947:Bacterial Secretion Systems; D001427:Bacterial Toxins; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; C000595441:KB001 antibody; D052899:Pore Forming Cytotoxic Proteins; C118546:antigen V, Pseudomonas