In a murine model of acute lung infection, airway administration of a therapeutic antibody confers greater protection than parenteral administration

Abstract

Due to growing antibiotic resistance, pneumonia caused by Pseudomonas aeruginosa is a major threat to human health and is driving the development of novel anti-infectious agents. Preventively or curatively administered pathogen-specific therapeutic antibodies (Abs) have several advantages, including a low level of toxicity and a unique pharmacological profile. At present, most Abs against respiratory infections are administered parenterally; this may not be optimal for therapeutics that have to reach the lungs to be effective. Although the airways constitute a logical delivery route for biologics designed to treat respiratory diseases, there are few scientific data on the advantages or disadvantages of this route in the context of pneumonia treatment. The objective of the present study was to evaluate the efficacy and fate of an anti-P. aeruginosa Ab targeting pcrV (mAb166) as a function of the administration route during pneumonia.

The airway-administered mAb166 displayed a favorable pharmacokinetic profile during the acute phase of the infection, and was associated with greater protection (relative to other delivery routes) of infected animals. Airway administration was associated with lower levels of lung inflammation, greater bacterial clearance, and recruitment of neutrophils in the airways.

In conclusion, the present study is the first to have compared the pharmacokinetics and efficacy of an anti-infectious Ab administered by different routes in an animal model of pneumonia. Our findings suggest that local delivery to the airways is associated with a more potent anti-bacterial response (relative to parenteral administration), and thus open up new perspectives for the prevention and treatment of pneumonia with Abs.

Introduction

Pneumonia (whether either community- or hospital-acquired) is a leading cause of morbidity, quality-adjusted life year loss, and mortality in children, adults, and the elderly. Furthermore, an alarming rise in levels of antimicrobial resistance is compromising the effective prevention and treatment of pneumonia. The opportunistic pneumonia-causing pathogens Pseudomonas aeruginosa (P. aeruginosa) is often associated with devastating, acute disease, and chronic infections [1,2]. Pseudomonas aeruginosa is one of the most prevalent infectious agents in intensive care units, and is the leading cause of ventilator-associated pneumonia in patients being treated for trauma or severe viral infections. Moreover, P. aeruginosa-associated lung infections are associated with significantly higher mortality than infections with other pathogens [3,4]. The prevention and treatment of P. aeruginosa infections are challenging, in view of the bacterium's genetic and biochemical versatility and intrinsic resistance to antibiotics [5]. Overall, the data show that the significant increase in antibiotic resistance over the last 15 years has been associated with greater premature mortality [6].

The low number of novel antibiotics coming onto the market means that novel alternative or complementary anti-infectious strategies are urgently needed. One such strategy involves the use of therapeutic antibodies (Abs), which have already proven successful in the prevention or treatment of infectious lung diseases. Three anti-infectious Abs have been approved for clinical use: the humanized IgG1 palivizumab for the prevention of respiratory syncytial virus infection in high-risk infants, and the human IgG1 raxibacumab and the chimeric IgG1 obiltoxaximab for the prophylaxis and/or treatment of pulmonary anthrax. Furthermore, 12 Abs targeting respiratory pathogens (including 4 Abs against P. aeruginosa) are in clinical development [7].

In the clinic, most therapeutic antibodies (and, indeed, most therapeutic proteins) are administered parenterally, i.e. via the intravenous (i.v.), subcutaneous (s.c.) or intramuscular (i.m.) route. Oral administration is not indicated because therapeutic proteins are not usually formulated to resist acid denaturation in the stomach or proteolytic degradation in the rest of the gastrointestinal tract. Most Abs for the treatment of respiratory tract infections are administered i.v. [7]. However, this route is unlikely to be optimal for therapeutic designed to treat respiratory diseases; the few available literature data indicate that only a small fraction of the injected Ab reaches the lungs/airways [[8], [9], [10]]. Given that large amounts of Ab are usually required to protect against infections, an Ab's systemic distribution after i.v. injection might limit efficacy while increasing the risk of systemic toxicity (serum thickening, cytokine release syndrome).

As the body's main entry portal for innocuous or harmful environmental antigens, the airways represent an attractive delivery route for drugs designed to treat respiratory diseases. We and others have recently demonstrated that the airway route is feasible for the delivery of Ab-based therapeutics [[11], [12], [13], [14], [15], [16], [17], [18]]. The Abs induce a treatment response, and pass slowly into the systemic circulation [[19], [20], [21], [22]]. Furthermore, it has been shown that Ab-based therapeutics are sensitive to aerosolization but can retain their physical and immunological properties when delivered with specific devices and after the addition of specific excipients [16].

Overall, the results of preclinical studies have shown that inhaled Abs are therapeutically active and thus underpin the growing interest in the pulmonary/airway route [7,23,24]. Nevertheless, the literature data on the advantages and disadvantages of parenteral versus local routes of anti-infective Ab administration are scarce. It is probably highly important to take account of situations in which the alveolus-capillary barrier is altered, since this might change the fate of and response to Abs. In the present study (performed in a murine model of acute pneumonia), we investigated the pharmacokinetics (PK) and protective activity of an archetypal anti-P. aeruginosa Ab as a function of its administration route. We found that airway administration of Ab was associated with a favorable PK profile, longer retention in the lung compartment, and a stronger anti-bacterial response by the host (characterized by enhanced neutrophil recruitment and bacterial clearance, and attenuated lung permeability). Local administration of Ab was also associated with a less intense acute inflammatory response, lower levels of pro-inflammatory cytokines.