Development of multispecific antibodies for the treatment of Pseudomonas aeruginosa infection

Abstract 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 IgG 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 T SS 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 we propose to characterize these anti bodies for their ability to bind P aeruginosa and block T SS 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 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 Narrative 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