Multifunctional Monoclonal Antibody Targeting Pseudomonas aeruginosa Keratitis in Mice

Abstract

A worrisome trend in the study and treatment of infectious disease noted in recent years is the increase in multidrug resistant strains of bacteria concurrent with a scarcity of new antimicrobial agents to counteract this rise. This is particularly true amongst bacteria within the Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) designation. P. aeruginosa is one of the most common causes of bacterial keratitis. Therefore, it is of vital importance to characterize new antimicrobial agents with anti-Pseudomonal activity for use with the ocular surface. MEDI3902 is a multifunctional antibody that targets the P. aeruginosa persistence factor Psl exopolysaccharide, and the type 3 secretion protein PcrV. We initially assessed this antibody for ocular surface toxicity. The antimicrobial activity of the antibody was then tested by treating mice with established P. aeruginosa keratitis with both topical and intravenous treatment modalities. MEDI3902, was shown to be non-toxic to the ocular surface of mice when given topically. It was also effective compared to the control antibody at preventing P. aeruginosa keratitis with a one-time treatment at the time of infection. Both topical and intravenous administration of MEDI3902 has been proved significant in treating established keratitis infections as well, speeding the resolution of infection significantly more than that of the control IgG. We report the first use of a topical immunotherapeutic multifunctional agent targeting Psl and type 3 secretion on the ocular surface as an antimicrobial agent. While MEDI3902 has been shown to prevent Pseudomonas biofilm formation in keratitis models when given prophylactically intravitally, we show that MEDI3902 has the capability to also treat an active infection when given intravenously to mice with Pseudomonas keratitis. Our data indicate antibodies are well tolerated and nontoxic on the ocular surface. They reduce infection in mice treated concurrently at inoculation and reduced the signs of cornea pathology in mice with established infection. Taken together, these data indicate treatment with monoclonal antibodies directed against Psl and PcrV may be clinically effective in the treatment of P. aeruginosa keratitis and suggest that the design of further antibodies to be an additional tool in the treatment of bacterial keratitis.

Clinical Features and Treatment Outcomes of Carbapenem-Resistant Pseudomonas aeruginosa Keratitis

“…45 Another collection of T3SS keratitis isolates favored epidemic clones of genes encoding exoU when compared with control patients. 46 The concerning progression in resistance and virulence of P aeruginosa highlights the need to explore alternative therapeutics, including new antibiotics, phage therapy, monoclonal antibodies, 47 and photodynamic therapy. Only cefiderocol, a last-resort siderophore cephalosporin, is indicated in in vitro susceptibility to these XDR isolates, but its use is limited as there is no current ocular preparation.…”

New alternative therapeutic strategies against Pseudomonas aeruginosa, an opportunistic multi-resistant pathogen with a myriad of virulence factors

“…Royal jelly is a secretion from young worker honeybees and contains nutrients for larvae development. It has been shown to inhibit PA biofilm formation by interacting with lectins and disrupting the initial attachment of PA to human lung epithelial cells in vitro [65]. Inhibition of lectin binding may be helpful in preventing and treating PA infections for its high stability and low risk of developing bacterial resistance.…”

“…Current research in managing PA infections has been directed toward preventing infection in high-risk patients with vaccines and modulation of virulence with monoclonal antibodies instead of focusing on bacterial clearance attainment [62]. The bispecific antibody MEDI3902 is under study (phase II) to prevent pyocyanic pneumonia [65]. It targets a protein secretion system (PcrV) and the exopolysaccharide PsI [65].…”

“…The bispecific antibody MEDI3902 is under study (phase II) to prevent pyocyanic pneumonia [65]. It targets a protein secretion system (PcrV) and the exopolysaccharide PsI [65]. An engineered human antibody Fab fragment that binds to the PAPcrV protein with high affinity has been identified and has potent in vitro neutralization activity against the TTSS.…”

Ocular Delivery of Predatory Bacteria with Cryomicroneedles Against Eye Infection

“…[ 10 ] P. aeruginosa and A. baumannii are responsible for keratitis resulting from trauma, contact lens wear, or ocular surgery. [ 11 ] K. pneumoniae may spread from the blood and cause endophthalmitis. [ 12 ] Finally, the therapeutic potential of this formulation was demonstrated in a mouse eye infection model ( E. coli as the pathogen), using topically applied B. bacteriovorus as the control.…”