Bacterial enzyme may be potent treatment for myasthenia gravis
CU43 found to work better than Vyvgart to disable self-reactive antibodies
A bacterial enzyme called CU43 potently mitigates the impact of the self-reactive antibodies that drive myasthenia gravis (MG) and other autoimmune diseases, according to data from a preclinical study.
The research team, led by scientists at Emory University in Georgia, in collaboration with researchers at Rockefeller University in New York, demonstrated in a mouse model that the enzyme was 4,000 times more potent at disabling self-reactive antibodies than the approved myasthenia gravis treatment Vyvgart (efgartigimod).
“The potency of this enzyme is quite remarkable when compared to current treatments for autoimmune diseases, and thus warrants consideration for further development for the treatment of this important class of diseases,” Jeffrey Ravetch, MD, PhD, a study co-author and the Theresa and Eugene M. Lang professor at Rockefeller, said in a university news story.
Eric Sundberg, PhD, the study’s senior author at Emory, added that “the enzymes we discovered can modify antibodies in such a way that they no longer cause disease.”
The discovery was detailed in “Potent efficacy of an IgG-specific endoglycosidase against IgG-mediated pathologies,” a study published in the journal Cell.
Looking for a new treatment for myasthenia gravis, other diseases
Several autoimmune diseases are characterized by self-reactive antibodies, also known as autoantibodies, that wrongly target healthy tissue, causing damage.
Autoimmune diseases are driven by the immune system’s abnormal production of these autoantibodies against healthy parts of the body, which results in damage to the body’s tissues.
In MG, self-reactive antibodies damage healthy proteins involved in nerve-cell communication, leading to the disease’s hallmark symptoms of muscle weakness and fatigue.
Immunoglobulin G, called IgG, is the most abundant class of antibody in the blood, and is also the one most commonly associated with autoimmune responses.
As such, certain approved therapies for autoimmune diseases, including MG, work to reduce IgG levels, either by removing them (plasmapheresis), blocking them (intravenous immunoglobulin), or promoting their destruction (FcRn blockers). Vyvgart is one of the FcRn blockers approved as a treatment for people with myasthenia gravis.
Suppressing IgG-mediated immune responses is also a strategy that certain microbes use to evade an attack by the host’s immune system. For example, a disease-causing bacterium called Streptococcus pyogenes secretes multidomain, or complex, enzymes called EndoS and EndoS2 that remove a specific sugar molecule, or glycan, from an IgG’s Fc region.
This disrupts the interaction between the IgG and other immune cells, and, in turn, the antibody’s ability to activate the immune system against a given invader.
Now, the team of researchers explored whether there were single-domain bacterial enzymes that specifically cleaved glycans from IgGs and could be used to treat autoimmune diseases caused by IgG self-reactive antibodies.
To that end, the researchers screened enzymes sharing similarities with EndoS and EndoS2’s domain specifically responsible for glycan removal. The team identified 10 produced by Corynebacteria that disabled IgG antibodies by selectively targeting and removing a glycan within the Fc region.
Among them, CU43 proved to be the most active, stable, and highly specific against a single type of glycan found solely on IgGs and not other classes of antibodies.
CU43 found to be 4,000 times more potent than Vyvgart against autoantibodies
The next step was to test CU43 in a mouse model developed by Ravetch’s lab, which also studies the Fc region of antibodies. These so-called humanized mice were genetically modified to produce human, instead of mouse, Fc receptor proteins.
In these animals, CU43 was found to effectively suppress antibody-mediated immune responses, and to be at least 4,000 times more potent than Vyvgart at doing so.
“These data demonstrate that [CU43] may provide equivalent clinical benefits as [Vyvgart] at significantly lower therapeutic doses,” the researchers wrote.
However, given a proxy animal model was used instead of an MG mouse model, there may be biological differences between these models that may provide different results, the team noted.
Rockefeller said in its release that the collaboration between the two universities “drew heavily on Ravetch’s expertise” with these mouse models.
According to Ravetch, “removing the glycan from the Fc region of autoantibodies with the enzyme discovered by the Emory group appears to be an effective strategy for reducing their [ability to cause disease].”
The researchers noted that CU43 also effectively mitigated other IgG-driven immune mechanisms in different mouse models. These included autoimmune hemolytic anemia, in which IgG antibodies bind to and destroy red blood cells, and IgG-dependent enhancement of certain viral diseases such as dengue fever.
Importantly, unlike current treatments for autoimmune diseases that often have immunosuppressive effects, CU43 represents a more targeted approach that specifically renders [self-reactive] antibodies inactive, while preserving important functions of protective antibodies necessary for host defense against [invaders].
Stylianos Bournazos, PhD, a study co-author and research associate professor in Ravetch’s lab, noted that CU43 is not only more potent but as more targeted.
“Importantly, unlike current treatments for autoimmune diseases that often have immunosuppressive effects, CU43 represents a more targeted approach that specifically renders [self-reactive] antibodies inactive, while preserving important functions of protective antibodies necessary for host defense against [invaders],” Bournazos said.
Sundberg said the team intends to advance its work as quickly as possible.
“We hope to leverage these promising results in mice to move this enzyme rapidly into clinical trials in humans,” Sundberg added. “It could potentially be used to treat a wide range of autoimmune diseases and other IgG-mediated [conditions], offering a powerful new approach to treating conditions that currently have limited therapeutic options.”
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