Using synthetic activity to design ultra-potent antibody cocktails

Here we show that transgenic spirulina may solve key challenges of developing effective monoclonal protein therapeutics for diseases afflicting gastrointestinal (GI) tissues. We describe, as a paradigm for this novel approach, LMN-201: an investigational four-component treatment for Clostridioides difficile (C. difficile) infection comprising four monoclonal protein therapeutics produced and delivered within spirulina biomass. Three antibody-like moieties within LMN-201 were rationally designed using a multiplicative potency framework, termed synthetic avidity, that increased in vitro toxin neutralization potency by >200-fold relative to the individual components. The fourth moiety, a lysin enzyme protein, adds direct, toxinotype-agnostic antibacterial activity. In rodent challenge models, species-relevant LMN-201-like cocktails reduced disease burden and mortality. In a human GI pharmacokinetic study, LMN-201 was present at concentrations 100- to 1,000-fold above the estimated minimally effective therapeutic threshold at the distal intestine. In a Phase 2 study in participants suffering from C. difficile infection (CDI), seven days of treatment with LMN-201 plus standard-of-care antibiotics achieved initial clinical cure in 21/21 (100%) participants, sustained clinical cure through four weeks in 19/21 (90.5%) participants, and had a favorable safety profile. These findings support LMN-201 with standard-of-care antibiotics as a viable treatment option for CDI, validate spirulina as a scalable platform for oral biologics, and establish a generalizable strategy for engineering high-potency combination protein therapeutics for diseases with a GI tissue nexus.