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Assessment of Panobacumab As Adjunctive Immunotherapy for the Treatment of Nosocomial Pseudomonas Aeruginosa Pneumonia

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Assessment of Panobacumab As Adjunctive Immunotherapy for the Treatment of Nosocomial Pseudomonas Aeruginosa Pneumonia Eur J Clin Microbiol Infect Dis DOI 10.1007/s10096-014-2156-1 ARTICLE Assessment of panobacumab as adjunctive immunotherapy for the treatment of nosocomial Pseudomonas aeruginosa pneumonia Y.-A. Que & H. Lazar & M. Wolff & B. François & P.-F. Laterre & E. Mercier & J. Garbino & J.-L. Pagani & J.-P. Revelly & E. Mus & A. Perez & M. Tamm & J.-J. Rouby & Q. Lu & J. Chastre & P. Eggimann Received: 25 January 2014 /Accepted: 5 May 2014 # Springer-Verlag Berlin Heidelberg 2014 Abstract The fully human anti-lipopolysaccharide (LPS) im- the full three-course panobacumab treatment, with a resolution munoglobulin M (IgM) monoclonal antibody panobacumab rate of 85 % (11/13) versus 64 % (9/14) (p=0.048). The was developed as an adjunctive immunotherapy for the treat- Kaplan–Meier survival curve showed a statistically significant- ment of O11 serotype Pseudomonas aeruginosa infections. ly shorter time to clinical resolution in this group of patients We evaluated the potential clinical efficacy of panobacumab (8.0 [IQR: 7.0–11.5] versus 18.5 [IQR: 8–30] days in those in the treatment of nosocomial pneumonia. We per- who did not receive the antibody; p=0.004). Panobacumab formed a post-hoc analysis of a multicenter phase IIa adjunctive immunotherapy may improve clinical outcome in a trial (NCT00851435) designed to prospectively evaluate shorter time if patients receive the full treatment (three doses). the safety and pharmacokinetics of panobacumab. Patients These preliminary results suggest that passive immunotherapy treated with panobacumab (n=17), including 13 patients re- targeting LPS may be a complementary strategy for the treat- ceiving the full treatment (three doses of 1.2 mg/kg), were ment of nosocomial O11 P. aeruginosa pneumonia. compared to 14 patients who did not receive the antibody. Overall, the 17 patients receiving panobacumab were more ill. They were an average of 72 years old [interquartile range Introduction (IQR): 64–79] versus an average of 50 years old (IQR: 30–73) (p=0.024) and had Acute Physiology and Chronic Health Pseudomonas aeruginosa is a recalcitrant, opportunistic Evaluation II (APACHE II) scores of 17 (IQR: 16–22) versus Gram-negative bacteria responsible for most nosocomial in- 15 (IQR: 10–19) (p=0.043). Adjunctive immunotherapy re- fections of critically ill patients [1–3]. The development of sulted in an improved clinical outcome in the group receiving multidrug resistance makes the treatment of infections caused Y.<A. Que : J.<L. Pagani : J.<P. Revelly : P. Eggimann (*) E. Mercier Adult Critical Care Service, Centre Hospitalier Universitaire Service de Réanimation Polyvalente and CRICS Network, CHRU de Vaudois, CHUV, Rue du Bugnon 46, 1011 Lausanne, Switzerland Tours, Tours, France e-mail: [email protected] J. Garbino H. Lazar : E. Mus : A. Perez Infectious Diseases, University Hospitals of Geneva, Geneva, Kenta Biotech, Schlieren, Switzerland Switzerland M. Wolff M. Tamm Réanimation Médicale et Infectieuse, Hopital Bichat-Claude Pneumonia Clinic, University Hospital Basel, Basel, Switzerland Bernard, AP-HP, Paris, France J.<J. Rouby : Q. Lu B. François Réanimation Polyvalente, Département d’Anesthésie-Réanimation, Intensive Care Unit, CIC-P 0801 Inserm, CHU Dupuytren, Limoges, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, France UPMC Paris 6, Paris, France P.<F. Laterre J. Chastre Intensive Care Unit, Saint-Luc University Hospital, UCL, Brussels, Service de Réanimation Médicale, Hôpital Pitié-Salpêtrière, AP-HP, Belgium Paris, France Eur J Clin Microbiol Infect Dis by this pathogen challenging [4, 5] and accounts for the were compared to a group of 14 patients screened in the study persistently high mortality rates observed in recent surveys that did not receive immunotherapy. [6, 7], despite aggressive supportive management [8, 9]. The number of new antimicrobials under clinical development remains extremely limited, and their introduction to the mar- Patients and methods ket is disappointingly slow [10], highlighting the urgency for innovative approaches to be developed for the management of Study population multidrug-resistant infections [11, 12]. Adjunctive passive immunotherapy specifically targeted at We performed a post-hoc analysis of the multicenter, open microbial products could be a promising strategy in overcom- pilot phase IIa clinical trial (NCT00851435) which prospec- ing this problem. Historically, passive immunotherapy using tively evaluated the safety and pharmacokinetics of at least anti-sera was successfully carried out before the antibiotic era one dose of 1.2 mg/kg panobacumab, a fully human mono- for the management of devastating infectious diseases, such as clonal anti-LPS IgM, given every 72 h in 17 patients with rabies and diphtheria [13]. The administration of intravenous microbiologically documented [bronchoalveolar lavage immunoglobulins as prophylaxis or as combination therapy (BAL), mini-BAL] serotype O11 P. aeruginosa pneumonia with antibiotics has shown promising results in treating sepsis [29]. Definitions and detailed inclusion/exclusion criteria are [14, 15]. The development of monoclonal antibodies (MAbs) described elsewhere [29]. These patients (intent-to-treat group) has improved antibody-based therapies by targeting specific and those receiving the full three-dose treatment (per-protocol virulence factors on respective pathogens. However, adjunc- group) were compared to a group consisting of patients who tive immunotherapy targeted at host response mediators has, fulfilled all the inclusion and exclusion criteria of the phase IIa so far, failed [16]. Therapies combining antimicrobials with study but who could not receive panobacumab (not treated MAbs targeted at bacterial targets may potentially result in a with panobacumab group) (Fig. 1) for the following reasons: more rapid resolution of infections, resulting in reductions in (i) treatment refusal (n=3); (ii) physicians refused to give the sepsis-related morbidity and mortality [17]. treatment (n=3); (iii) patients were screened after the end of the The membrane-bound virulence factor lipopolysaccharide trial (n=3); (iv) delayed serotyping results (n=2); or (iv) un- (LPS), expressed by all Gram-negative bacteria like known reasons (n=3). P. aeruginosa, elicits an immunoglobulin M (IgM)-mediated antibody response that takes several days to fully develop, and this delay may increase the risk of death in severe infections Data collection [18]. Human monoclonal antibodies directed against P. aeruginosa LPS have demonstrated protection in various In addition to demographics (age, gender), the general condi- settings [19–21]. Panobacumab is a fully human monoclonal tion of the patients was evaluated using the Acute Physiology antibody of the IgM/κ isotype directed against the LPS O- and Chronic Health Evaluation II (APACHE II) score system polysaccharide moiety of P. aeruginosa O11 [22, 23]. [30]. Organ dysfunction was evaluated using the Sequential P. aeruginosa international antigenic scheme serotypes O11 Organ Failure Assessment (SOFA) score [31]. The severity of and O6 have been reported to be the most prevalent serotypes pneumonia was assessed using the Clinical Pulmonary Infec- among epidemiological studies [24, 25]. Strains exhibiting tion Score (CPIS) [32]. exotoxin U, a potential virulence factor, were frequently serotyped as O11 [25, 26]. In an experimental model of Clinical endpoints pneumonia, serotype O11 was found to be associated with increased lung injury [27]. These epidemiological data were The clinical endpoints were as follows: (i) survival defined as confirmed by a recent retrospective cohort study on 123 survival by day 30; (ii) clinical resolution was defined as no patients with nosocomial P. aeruginosa pneumonia, in which persisting symptoms or complications attributable to the pneu- O6 (29 %) and O11 (23 %) were the most prevalent serotypes monia with a return to normal values of all four of the [28]. In this study, serotype O11 was associated with increased following: core body temperature (<38.3 °C), peripheral 3 3 persisting pneumonia and decreased clinical resolution com- blood leucocyte count (<10 × 10 /mm ), PaO2/FIO2 ratio pared to other serotypes. Preliminary data from an open phase (>25 kPa), and no or minimal growth of bacteria similar to IIa study demonstrated the safety of panobacumab in critically those isolated from mini-BAL samples in quantitative cultures ill patients presenting with P. aeruginosa O11 nosocomial of endotracheal aspirates; (iii) time to clinical resolution was pneumonia [29]. We performed a post-hoc analysis of this defined as free of pneumonia and recurrence (relapse caused study to evaluate the potential clinical efficacy of by the same pathogen) at day 30 post-treatment; (iv) recur- panobacumab in the treatment of P. aeruginosa O11 nosoco- rence was defined as resolution of all clinical signs of pneu- mial pneumonia. The 17 patients that received panobacumab monia, including infiltrates, with a subsequent return of Eur J Clin Microbiol Infect Dis Fig. 1 Flow chart of patients included in the post-hoc analysis clinical signs and a diagnostic culture; (v) death was scored as II scores (17 [IQR: 16–22) versus 15 [IQR: 10–19]; p=0.043). a non-resolved infection. The severity of pneumonia and the characteristics of antibiotic treatment were comparable among treated and untreated Statistical analysis patients. Statistical analyses compared patients that received at Outcome least one dose or three doses of panobacumab to control
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