Antibacterial Monoclonal Antibodies Do Not Disrupt the Intestinal Microbiome or Its Function.

Antibiotics revolutionized the treatment of infectious diseases; however, it is now clear that broad-spectrum antibiotics alter the composition and function of the host's microbiome. The microbiome plays a key role in human health, and its perturbation is increasingly recognized as contributing to many human diseases. Widespread broad-spectrum antibiotic use has also resulted in the emergence of multidrug-resistant pathogens, spurring the development of pathogen-specific strategies such as monoclonal antibodies (MAbs) to combat bacterial infection. Not only are pathogen-specific approaches not expected to induce resistance in nontargeted bacteria, but they are hypothesized to have minimal impact on the gut microbiome. Here, we compare the effects of antibiotics, pathogen-specific MAbs, and their controls (saline or control IgG [c-IgG]) on the gut microbiome of 7-week-old, female, C57BL/6 mice. The magnitude of change in taxonomic abundance, bacterial diversity, and bacterial metabolites, including short-chain fatty acids (SCFA) and bile acids in the fecal pellets from mice treated with pathogen-specific MAbs, was no different from that with animals treated with saline or an IgG control. Conversely, dramatic changes were observed in the relative abundance, as well as alpha and beta diversity, of the fecal microbiome and bacterial metabolites in the feces of all antibiotic-treated mice. Taken together, these results indicate that pathogen-specific MAbs do not alter the fecal microbiome like broad-spectrum antibiotics and may represent a safer, more-targeted approach to antibacterial therapy.

Detecting bliss synergy in in vivo combination studies with a tumor kinetic model.

Linear models are generally reliable methods for analyzing tumor growth in vivo, with drug effectiveness being represented by the steepness of the regression slope. With immunotherapy, however, not all tumor growth follows a linear pattern, even after log transformation. Tumor kinetics models are mechanistic models that describe tumor proliferation and tumor killing macroscopically, through a set of differential equations. In drug combination studies, although an additional drug-drug interaction term can be added to such models, however, the drug interactions suggested by tumor kinetics models cannot be translated directly into synergistic effects. We have developed a novel statistical approach that simultaneously models tumor growth in control, monotherapy, and combination therapy groups. This approach makes it possible to test for synergistic effects directly and to compare such effects among different studies.