Harnessing endogenous anti-glycan antibodies using a novel, bifunctional immunotherapy to treat gram-negative...

The current array of traditional antibacterial agents targeting Gram-negative infections are failing to meet the clinical need. Here we present a novel, bifunctional immunotherapy (CTX-09) with the ability to harness endogenous anti-galactose-alpha-1,3-galactosyl-beta-1,4-N-acetyl-glucosamine (anti-αGal) antibodies to drive immune-mediated clearance of Gram-negative bacteria. In addition, CTX-09 has direct-acting broad-spectrum bactericidal activity equivalent to colistin and meropenem against 1952 Gram-negative clinical isolates. In vitro, CTX-09 demonstrated immune-mediated efficacy through recruitment of anti-αGal antibodies and engagement of antibody effector mechanisms that enhanced bacterial clearance at sub-bactericidal concentrations. In vivo, at sub-bactericidal doses, CTX-09 demonstrated anti-αGal antibody driven clearance of susceptible and multidrug-resistant (MDR) strains. In the presence of anti-αGal antibody, bacterial burden was reduced by >99.9% (3-log10) in neutropenic mouse thigh and pneumonia infection models. This data suggest that CTX-09 or other antibody-recruiting molecules have potential to address the urgent clinical need of patients with gram-negative infections using a novel immunotherapeutic mechanism.