Engineered antibodies targeted to bacterial surface integrate effector functions with toxin neutralization to provide superior efficacy against bacterial infections

Rajan P. Adhikari, Farhang Alem, Daniel Kemboi, Tulasikumari Kanipakala, Shardulendra P. Sherchand, Shweta Kailasan, Bret K. Purcell, Henry S. Heine, Kasi Russell-Lodrigue, Irina Etobayeva, Katie A. Howell, Hong Vu, Sergey Shulenin, Frederick W. Holtsberg, Chad J. Roy, Ramin M. Hakami, Daniel C. Nelson, M. Javad Aman
2024 · doi:10.1101/2024.09.23.24313920
preprint OA: closed
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Abstract

Anti-bacterial monoclonal antibody (mAb) therapies either rely on toxin neutralization or opsonophagocytic killing (OPK). Toxin neutralization protects the host from toxin-induced damage, while leaving the organism intact. OPK inducing antibodies clear the bacteria but leave the released toxins unencountered. Infection site targeted anti-toxin antibodies (ISTAbs) that we report here addresses this binary paradigm by combining both functionalities into a single molecule. ISTAbs consist of cell wall targeting (CWT) domains of bacteriophage endolysins fused to toxin neutralizing mAbs (IgG). CWT governs specific binding to the surface of bacteria while the IgG variable domain neutralizes the toxins as they are released. The complex is then cleared by phagocytic cells. As proof of concept, we generated several ISTAb prototypes targeting major toxins from two Gram-positive spore forming pathogens that have a high clinical significance; Clostridium difficile , causative agent of the most common hospital-acquired infection, and Bacillus anthracis , a Category A select agent pathogen. Both groups of ISTAbs exhibited potent toxin neutralization, binding to their respective bacterial cells, and induction of opsonophagocytosis. In mice infected with B. anthracis , ISTAbs exhibit significantly higher efficacy than parental IgG in both pre- and post-challenge models. Furthermore, ISTAbs fully protected against B. anthracis infection in a nonhuman primate (NHP) aerosol challenge model. These findings establish that as a platform technology, ISTAbs are broadly applicable for therapeutic intervention against several toxigenic bacterial pathogens.

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