[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
Penetration of a Monoclonal Antibody Combination (ASN100) Targeting S. aureus Cytotoxins in Lung Epithelial Lining Fluid: A Randomized, Double-blind, Placebo-controlled, Single Ascending Dose Study in Healthy Volunteers.
Zoltan Magyarics, Fraser Leslie, Johann Bartko, Harald Rouha, Steven Luperchio, Christian Schörgenhofer, Michael Schwameis, Ulla Derhaschnig, Heimo Lagler, Leopold Stiebellehner,Christa Firbas, Susanne Weber, Ed Campanaro, Bernd Jilma, Eszter Nagy, Chris Stevens
ASN100 is a novel antibody combination of two fully human IgG1 kappa monoclonal antibodies, ASN-1 and ASN-2 which neutralize six Staphylococcus aureus cytotoxins, alpha-hemolysin (Hla) and five bi-component leukocidins. We assessed the safety, tolerability, and serum and lung pharmacokinetics of ASN100 in a randomized, double-blind, placebo-controlled single dose escalation first-in-human study.
Fifty-two healthy volunteers were enrolled and randomized to receive either ASN-1, ASN-2, or a combination of both mAbs (ASN100), or corresponding placebo. Thirty-two subjects in the double-blind dose escalation portion of the study received ASN-1 or ASN-2 at a 200, 600, 1800, or 4000 mg dose, or placebo. Eight subjects received both mAbs simultaneously in a 1:1 ratio (ASN100) at 3600 or 8000 mg, or placebos. Twelve additional subjects received open-label ASN100 at 3600 or 8000 mg to assess the pharmacokinetics of ASN-1 and ASN-2 in epithelial lining fluid (ELF) by bronchoalveolar lavage fluid sampling. Subjects were followed 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 PK with a half-life of approximately three 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 post-dosing.
The favorable safety profile, ELF penetration, and maintained functional activity in serum supported the further clinical development of ASN100.
Copyright © 2019 Magyarics et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Keywords: Antibiotics; Staphylococcus aureus; Monoclonal antibodies.