Gram-negative pathogens are responsible for more than half of all hospital-acquired infections, including some of the most lethal nosocomial infections, bloodstream infections, and bacterial pneumonias. Historically, discovering new antibiotics against Gram-negative bacteria has proven to be particularly difficult. Arsanis is applying a targeted monoclonal antibody approach to combat infections caused by multi-drug resistant strains of the Gram-negative pathogens Escherichia coli and Klebsiella pneumoniae to overcome the limitations of current antibiotics.
ASN200: A Monoclonal Antibody Program Targeting Multi-drug Resistant Escherichia coli
Addressing the Unmet Medical Need Caused by Drug-resistant Extra-intestinal Escherichia coli Infections
Extra-intestinal pathogenic Escherichia coli (ExPEC) is the most common Gram-negative bacterial pathogen in humans. ExPEC is responsible for the majority of urinary tract infections (UTIs) and is a significant contributor to other life-threatening infections, including bloodstream infections (BSI), intra-abdominal infections (IAI), ventilator-associated bacterial pneumonia (VABP), and neonatal meningitis. Increasing multi-drug resistance among ExPEC strains is a major obstacle to treatment, leading to increased hospitalizations, healthcare costs, and mortality.
A particular hyper-virulent multi-drug resistant clonal lineage of E. coli, ST131-O25b:H4, has emerged and spread globally in both the hospital and the community. This clone exhibits a rare combination of traits. Besides its multi-drug resistant phenotype, ST131-O25b:H4 exhibits considerably high virulence and fitness and an alarming ability to spread between humans and animals.
The progressive acquisition of resistance in E. coli ST131-O25b:H4 strains leaves very few effective antibiotics for treatment of infected patients. More alarming is the recent appearance of isolates resistant to carbapenems and other last-resort antibiotics, including colistin. The potential emergence and the threat of the subsequent spread of pan-drug resistant E. coli strains calls urgently for surveillance and the development of alternative therapeutic and preventative approaches.
The ASN200 program is currently in preclinical development. Within this program, Arsanis discovered a unique monoclonal antibody, ASN-4, that has multiple modes of action against E. coli ST131-O25b:H4. ASN-4 is directly bactericidal and provides anti-inflammatory effects without the need for innate immune cells and therefore has the potential to be beneficial even in immunocompromised patients. In addition, ASN-4 potentiates the activity of antibiotics, potentially minimizing the use of last-line antibiotics with less favorable toxicity profile (e.g., colistin). ASN-4 is highly potent and elicits a high level of protection at very low doses in relevant animal models and therefore has the potential to be used both for prevention of disease in colonized, high-risk patients and treatment of serious infections, including those where antibiotics have failed.
ASN300: A Monoclonal Antibody Program Targeting Klebsiella pneumoniae
Unmet Medical Need Due to Carbapenem-resistant Klebsiella pneumoniae Infections.
Multi-drug resistant K. pneumoniae is an increasing concern worldwide. Currently, about 25% of all K. pneumoniae isolates in the US express an extended-spectrum beta-lactamase (ESBL) enzyme and ~10% are also carbapenem-resistant. Outside of the US, K. pneumoniae resistance to carbapenems is even greater, with rates of 65% in Greece, 55% in India, and 35% in Italy. For these carbapenem-resistant K. pneumoniae (CRKP), the only remaining treatment options are antibiotics of last resort such as tigecycline and colistin that have unfavorable toxicity profiles and/or sub-optimal efficacy.
For the ASN300 program, currently set to enter preclinical development, Arsanis is developing monoclonal antibodies targeting K. pneumoniae surface structures that exhibit limited diversity. These monoclonal antibodies have rapid and targeted activity through different modes of action and provide high efficacy in relevant animal models of severe K. pneumoniae infections. The ASN300 program has potential clinical applications in both treatment and pre-emptive indications.