Pseudomonas aeruginosa is a major pathogen that causes a wide range of hospital- and community- acquired infections. The greatest obstacle to treating these infections is antibiotic resistance; the rising preva- lence of multidrug-resistant (MDR) P. aeruginosa is a major public health concern. Thus, there is an urgent need to develop novel therapeutics, which can circumvent drug resistance mechanisms applied by bacteria. Inhibrx has developed a platform based on single domain antibodies (sdAb) to enable development of novel antibiotics based on different mechanisms of action to circumvent the development of resistance. This platform is a modular format wherein multiple camelid heavy chain only antibody binding domains are joined end to end, together with an effector domain (Fc), to create multi-specific, multivalent antibodies targeting multiple epitopes. We propose to develop a therapeutic antibody against P. aeruginosa that simultaneously targets mul- tiple secreted toxins as well as a cell-surface target, in a molecule that also contains a functional human IgG1 Fc domain. Inhibrx has used its versatile antibody format to develop two lead hexavalent, tri-specific, human- ized molecules with specificity against two epitopes of a crucial component of the T3SS virulence mechanism and against an outer membrane lipoprotein that is highly conserved in all P. aeruginosa strains. These antibod- ies bind to all Pseudomonas strains tested and show improved efficacy in a murine infection model compared to the current leader in potential anti-Pseudomonas antibody therapeutics. We hypothesize that a therapeutic based on these antibodies will prove superior to all other existing P. aeru- ginosa therapeutics. Toxin blocking functionality is expected to protect immune cells recruited to the site of in- fection, while cell binding ?capability will enable opsonization of the bacteria, followed by their phagocytosis and clearance by the immune system. ?In this project we seek to take our candidate antibodies through Investiga- tional New Drug (IND) enabling toxicology. In Phase I (Specific Aim #1) we propose to characterize these anti- bodies for their ability to bind P. aeruginosa and block T3SS dependent cytotoxicity in vitro and to compare their efficacy in in vivo models of infection, establishing one of them as a clinical candidate. Phase II of this pro- ject will focus on performing IND enabling research to facilitate taking the candidate antibody selected in Phase I to clinical trials. Pharmacokinetics (PK) will first be tested in Specific Aim #2 in human FcRn transgenic mice, as human antibodies generally have relatively short half-lives in wildtype rodents. IND-enabling multi-dose tox- icity studies will then be performed in non-human primates (NHPs) to determine safety and PK of our clinical candidate. At the conclusion of this project, Inhibrx will have developed a much needed antibody therapeutic for treating MDR Pseudomonas that will be ready for IND filing. We expect this therapeutic to be highly im- pactful and transformative for MDR P. aeruginosa infections.
Pseudomonas aeruginosa is a major pathogen that causes a wide range of hospital- and community- acquired infections. The greatest obstacle to treating these infections is antibiotic resistance; the rising preva- lence of multidrug-resistant (MDR) P. aeruginosa is a major public health concern. Through the research proposed under this grant, we propose to advance a novel antibody that combines toxin blocking and bacte- rial cell-surface capabilities as a best-in-class anti-P. aeruginosa therapeutic antibody. ?We expect this ther- apeutic to be highly impactful and transformative for MDR P. aeruginosa infections.
