In vitro and in vivo properties of a fully human IgG1 monoclonal antibody             that combats multidrug resistant Pseudomonas aeruginosa.
The development of an anti-bacterial drug in the form of a monoclonal antibody (mAb) targeting an exposed virulence factor, represents an innovative therapeutic strategy. Consequently, a fully human IgG1 mAb (LST-007) targeting Pseudomonas aeruginosa (PA) flagellin type b was recombinantly expressed and characterized in vitro and in an infection model driven by a multidrug resistant (MDR) PA strain. LST-007 demonstrated a highly specific binding towards whole PA bacteria harboring flagellin type b and its recombinant counterpart, with a K(D) of 7.4x10(-10) M. In bioactivity assays, LST-007 or titers of Cmax sera derived from pharmacokinetic studies, markedly attenuated PA motility in an equipotent manner. In vivo, parenteral LST-007 (20 mg/kg) given as a single or double-dosing paradigm post-infection, afforded survival (up to 75% at Day 7) in a lethal model of pneumonia driven by the intratracheal (i.t.) instillation of an LD(80) of the MDR PA isolate. This protective effect was markedly superior to that of imipenem (30% survival at Day 7) and totally devoid with an irrelevant, human isotype mAb. These data lay credence that LST-007 may be a valuable adjunct to the limited list of anti-bacterials that can tackle MDR PA strains, thereby warranting its continued development for eventual clinical evaluation.
Lostam BioPharmaceuticals, Nazareth, Israel.
Azmi
A
Adawi
Carlo
C
Bisignano
Tiziana
T
Genovese
Angela
A
Filocamo
Camellia
C
Khouri-Assi
Anat
A
Neville
Giora Z
GZ
Feuerstein
Salvatore
S
Cuzzocrea
Lewis F
LF
Neville
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016466:CHO Cells; D006224:Cricetinae; D024901:Drug Resistance, Multiple, Bacterial; D005408:Flagellin / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D051379:Mice; D011014:Pneumonia / Q000178:diet therapy / Q000276:immunology / Q000401:mortality; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D005408:Flagellin; C416532:flaB flagellin