(A) Genetic characterization and source. by bronchoalveolar lavage fluid sampling. Subjects were monitored for 98?days (double-blind cohorts) or 30?days (open-label cohorts) for safety assessment. No dose-limiting toxicities were observed, and all adverse events were mild and transient, with only two adverse events considered possibly related to the investigational product. ASN100 exhibited linear serum pharmacokinetics with a half-life of approximately 3 weeks and showed detectable penetration into the ELF. No treatment-emergent anti-drug antibody responses were detected. The toxin neutralizing potency of ASN100 in human serum was confirmed up to 58?days postdosing. The favorable safety profile, ELF penetration, and maintained functional activity in serum supported the further clinical development of ASN100. KEYWORDS: ASN100, phase 1, cytotoxins, anti-infective monoclonal antibodies, epithelial lining fluid pharmacokinetics, first-in-human trial INTRODUCTION (R)-Rivastigmine D6 tartrate Monoclonal antibodies (MAbs) are established as safe and effective biologics for both the treatment and prevention of disease. To date, over 60 MAbs have received regulatory approval, including those used for both the treatment and the prevention of infectious diseases (1,C3). is a human pathogen capable of causing infections ranging from mild conditions to severe diseases such as pneumonia and sepsis (4). produces a multitude of cytotoxins that target epithelial cells and white blood cells (5, 6). Neutralization of cytotoxins is viewed as a potential preemptive and therapeutic modality against staphylococcal infections (7). ASN100 is a novel combination of two fully human IgG1() MAbs, ASN-1 and ASN-2, that together neutralize six cytotoxins contributing to pneumonia pathogenesis. ASN-1 neutralizes alpha-hemolysin (Hla or alpha toxin) and four bicomponent leukocidins: LukSF-PV Mouse monoclonal to HSV Tag (Panton-Valentine leukocidin), LukED, and two gamma-hemolysins HlgAB and HlgCB. ASN-2 neutralizes the fifth leukocidin, LukGH (also known as LukAB). Both MAbs demonstrated potent neutralizing activity in cell-based functional assays against target toxins (8, 9). They inhibit the assembly of pore complexes into target cell membranes but do not recognize toxin molecules after receptor binding (8,C10). ASN-1 showed full protection in a lethal pneumonia rabbit model (11), which was dependent on the neutralization of both Hla and bicomponent leukocidins (12, 13). In the same model, an Hla-only specific MAb protected only 25 to 33% of animals at a dose range of 10 to 30?mg/kg, while ASN100 afforded 100% survival against lethal challenge with a USA300 CA-MRSA at a 10?mg/kg dose (11, 13). RESULTS Investigational product administration and adverse events. A total of 52 subjects were dosed between November 2015 and May 2016. Ten subjects received placebo, and 42 received ASN-1, ASN-2, or ASN100; exposure to the investigational product (IP) is summarized in Fig. 1. All 52 subjects attended all study visits and successfully completed the study. Subject demographics are summarized in Table 1 . Open in a separate window FIG 1 Flow chart of participant enrollment in the ASN100-01 trial outlines the disposition of subjects enrolled in the study, including screen failures and randomized subjects, as well as exposure to the study drug. TABLE 1 Subject demographics and baseline characteristics= 10)= 12)= 12)= 6)= 12)= 10)= 9*)= 6)= 9*)= 12)= 12)= 18?)= 6= 6= (R)-Rivastigmine D6 tartrate 6= 6)100 (10.3)165 (114)17,948 (22.0)24,242 (17.9)19,411 (21.7)25,751 (17.6)0.0107 (24.8)0.00793 (17.9)6.89 (3.1)6.58 (24.4)25.3 (28.4)23.9 (0.7)????600 mg (= 6)185 (13.5)183 (18.7)60,515 (13.5)67,100 (34.6)64,516 (16.3)70,440 (35.5)0.0095 (15.3)0.00936 (38.9)6.63 (18.8)6.10 (21.6)25.0 (32.4)31.3 (16.6)????1,800 mg (= 6)578 (41.3)453 (4.9)172,066 (38.9)244,728 (19.4)183,930 (41.6)269,507 (20.1)0.0108 (33.5)0.00686 (19.4)8.02 (32.3)6.38 (12.3)24.0 (20.1)28.3 (10.9)????4,000 mg (= 6)1,868 (3.5)1,342 (R)-Rivastigmine D6 tartrate (5.5)339,474 (15.6)530,058 (10.1)351,387 (15.1)593,307 (9.6)0.0116 .(154)0.00678 (9.6)7.00 (32.2)6.78 (13.7)19.7 (31.9)32.8 (23.1)ASN100????3,600 mg (= 3)550 (20.6)468 (0.7)201,134 (132.2)250,887 (21.9)213,265 (14.1)296,315 (21.7)0.0086 (15.0)0.00627 (21.6)6.89 (7.5)7.55 (21.6)24.1 (4.3)36.3 (17.4)????3,600 mg (= 6), open label638 (25.1)372 (11.8)NANA135,631 (15.8)151,232 (13.8)0.0136 (18.5)0.01207 (11.8)6.37 (33.8)9.4 (12.7)14.0 (26.2)22.8 (23.5)????8,000 mg (= 3)975 (12.7)1,075 (12.7)302,392 (16.7)437,901 (13.2)316,427 (18.6)503,209 (20.1)0.0130 (18.3)0.00816 (19.5)8.24 (7.6)8.26 (10.8)20.3 (14.9)32.3 (31.3)????8,000 mg (= 6), open label1,252 (33.0)1,095 (16.5)NANA342,449 (29.2)382,996 (19.5)0.0124 (23.5)0.01078.