Anti-S. aureus mAbtyrin Biologic Targets Multiple Bacterial Virulence ... - Genetic Engineering & Biotechnology News

Early studies in animal models have demonstrated how a bioengineered antibacterial drug candidate can counter infection with Staphylococcus aureus—including drug-resistant strains that represent a major cause of death in hospitalized patients. The therapeutic candidate, SM1B74, is a human-derived multivalent anti-S. aureus monoclonal antibody (mAb)-centyrin fusion protein—an mAbtyrin—which in tests reported by researchers at NYU Grossman School of Medicine and at Janssen Biotech was found to be more effective than a standard antibiotic drug at treating mice infected with S. aureus, including resistant MRSA strains. SM1B74 also worked in synergy with the antibiotic vancomycin to increase pathogen clearance in an animal model of bacteremia.

The experimental treatment targets ten disease-causing mechanisms exploited by S. aureus, but without killing the organism. This approach, the researchers suggested, could help to address antibiotic resistance, whereby antibiotics kill vulnerable strains first, only to make more space for other strains that happen to be less vulnerable, until the drugs no longer work.

"To our knowledge, this is the first report showing that mAbtyrins can drastically reduce the populations of this pathogen in cell studies, and in live mice infected with drug-resistant strains so common in hospitals," said lead study author Victor Torres, PhD, the C.V. Starr professor of microbiology and director of the NYU Langone Health Antimicrobial-Resistant Pathogen Program. "Our goal was to design a biologic that works against S. aureus inside and outside of cells, while also taking away the weapons it uses to evade the immune system."

Torres and colleagues reported on their studies in Cell Host & Microbe, in a paper titled, "Multivalent human antibody-centyrin fusion protein to prevent and treat Staphylococcus aureus infections," in which they concluded, "SM1B74 serves as an example of the many possibilities for engineering multivalent antibody biologics."

About one-third of the human population carries S. aureus without symptoms, but individuals with weakened immune systems, and particularly hospitalized patients, may develop life-threatening lung, heart, bone, or bloodstream infections. "S. aureus is a human commensal bacterium that can cause a wide spectrum of diseases," the authors explained. "These range from mild and usually self-limiting conditions such as skin and soft tissue infections (SSTIs) to severe life-threatening diseases such as pneumonia, endocarditis, and sepsis." Approved antibiotics for severe S. aureus infections often can't completely clear the pathogen, and methicillin-resistant strains of S. aureus are of particular concern. Centers for Disease Control figures cited by the researchers indicated that in 2019 there were 323,700 cases of diagnosed, severe infections mediated by methicillin-resistant S. aureus (MRSA) in hospitalized patients in the United States, resulting in 10,600 deaths. This, the authors noted, "… was among the highest case fatality rate of all bacterial pathogen threats identified."

The antibacterial mAbtyrin candidate SM1B74 is based on an engineered version of a human monoclonal antibody that marks S. aureus for uptake and destruction by immune cells. Attached to the mAb are centyrins, small proteins that prevent these bacteria from boring holes into the human immune cells in which they hide. As the invaders multiply, these cells die and burst, eliminating their threat to the bacteria.

The new study reported by Torres and colleagues is the culmination of a five-year research partnership between scientists at NYU Grossman School of Medicine and Janssen to address the unique nature of S. aureus. In 2019, the NYU Langone team together with Janssen researchers, published a study that found that centyrins interfere with the action of potent toxins used by S. aureus to bore into immune cells. The authors further explained, "… S. aureus produces many membrane-damaging toxins that contribute to the pathogen's virulence potential. Strains associated with human infections can produce up to five pore-forming bicomponent leukocidins …These bicomponent leukocidins are potent killers of human phagocytes such as neutrophils and antigen-presenting cells, and they impact the development of adaptive immunity in murine models of S. aureus recurrent infection."

For their research, the investigators used a molecular biology technique to make changes in a single parental centyrin, instantly creating a trillion slightly different versions of it via automation. Screening the resulting library revealed a small set of centyrins that cling more tightly to the toxins, blocking their function.

Building on this work, the team fused the centyrins to a mAb originally taken from a patient recovering from S. aureus infection. Already primed by its encounter with the bacteria, the mAb could label the bacterial cells such that they are engulfed into pockets within the immune system's phagocytes. That is, unless the same toxins that enable S. aureus to drill into immune cells from the outside let it drill out of the pockets to invade from the inside.

Part of the resulting bioengineered mAbtyrin serves as the passport that is recognized by the immune cells, which then engulf the entire, attached mAbtyrin, along with its centyrins, and fold it into the pockets along with bacteria. Once inside, the centyrins block the bacterial toxins there. This, suggest the authors, sets their effort apart from antibody combinations that target the toxins only outside of cells. "SM1B74 serves as a Trojan horse that brings toxin-neutralizing centyrins into the phagolysosome to protect neutrophils from toxin-mediated intracellular lysis, another key property that separates our molecule from other mAbs," they wrote.

The team made several additional changes to their S. aureus-targeting mAbtyrin by, for example, activating chain reactions that amplify the immune response, as well as by preventing certain bacterial enzymes from cutting up antibodies and others from gumming up their action. "We aimed to engineer a multivalent mAb-fusion biologic that avoids many of the strategies used by S. aureus to subvert antibody-mediated antimicrobial functions," they explained.

For their in vitro experiments, the researchers tracked the growth of S. aureus strains commonly occurring in U.S. communities in the presence of primary phagocytes. They found that bacterial populations grew almost normally in the presence of the parental antibody, slightly less well in the presence of the team's engineered mAb, and half as fast when the mAbtyrin was used.

Working in mouse models of S. aureus infection, the team then demonstrated that 98% of animals treated with a control mAb (no centyrins) developed bacteria-filled sores on their kidneys when infected with a deadly strain of S. aureus, while only 38% of mice did so when treated with the mAbtyrin. Further, when these tissues were removed and colonies of bacteria in them counted, the mice treated with the mAbtyrin had one hundred times (two logs) fewer bacterial cells than those treated with a control mAb.

Finally, the team showed that a combination of small doses of the antibiotic vancomycin with the mAbtyrin in mice significantly improved the efficacy of the mAbtyrin, resulting in maximum reduction of bacterial loads in the kidneys and greater than 70% protection from kidney lesions. Torres noted, "It is incredibly important that we find new ways to boost the action of vancomycin, a last line of defense against MRSA."

The authors further concluded, "Collectively, SM1B74 can target five surface proteins and can subvert the action of five different S. aureus virulence factors. We demonstrated that the combination of all of these components is critical for the observed reduced pathology, bacterial burden, and lethality in preclinical models of infection … these studies demonstrate the potential therapeutic benefit associated with the use of SM1B74 as an adjunct to vancomycin therapy in the prophylaxis of invasive S. aureus infections."

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