New discovery revolutionizes treatment of autoimmune disorders
A groundbreaking enzyme discovery targets harmful IgG antibodies, offering hope for autoimmune disease treatment and reduced side effects.
Eric Sundberg, professor and chair in the Department of Biochemistry at Emory University School of Medicine, was principal investigator on the study. (CREDIT: Emory University)
A breakthrough discovery in enzyme science could revolutionize the treatment of autoimmune disorders and other diseases tied to the overactivity of antibodies.
Published in the journal, Cell, scientists at Emory University have unveiled a family of enzymes secreted by pathogenic corynebacterial species that target and neutralize the disease-causing effects of immunoglobulin G (IgG) antibodies. Among these, a single-domain endoglycosidase (ENGase) called CU43 stands out for its exceptional therapeutic potential.
IgG antibodies play a pivotal role in the immune response, helping to identify and neutralize pathogens. However, in some cases, they also contribute to autoimmune diseases, such as myasthenia gravis (MG), by attacking the body’s own cells.
At the heart of these interactions is the Asn297-linked glycan on the Fc region of IgG antibodies. This glycan facilitates binding to Fc receptors, triggering immune responses. The newly identified ENGases, including CU43, specifically hydrolyze this glycan, disrupting these interactions and mitigating harmful immune activity.
Previously, IgG-specific ENGases like EndoS and EndoS2—produced by Streptococcus pyogenes—were known for their ability to target IgG antibodies. These enzymes are multi-domain proteins with distinct structural features that enable precise activity on IgG glycans. The corynebacterial ENGases, by contrast, exhibit a simpler single-domain architecture while retaining similar specificity and efficacy.
Using advanced sequence similarity network (SSN) analysis and structural modeling, researchers identified 10 corynebacterial-derived ENGases. These enzymes, including CU43, are part of a clade associated with pathogenic corynebacterial species like Corynebacterium ulcerans. Their GH18 catalytic domains—typical of glycoside hydrolases—exhibit strict specificity for IgG glycans.
Most of these ENGases are secreted via the general secretory (Sec) system, but some, like CX35, utilize the twin arginine translocation (Tat) pathway. Structural studies revealed a conserved active-site motif (DGxDxDxE) across these enzymes, ensuring precise catalytic activity.
Notably, CX35 showed broader activity, processing both IgG and non-IgG substrates, whereas other enzymes, such as CU43, demonstrated exclusive IgG specificity.
Further studies highlighted the structural simplicity of these enzymes. Unlike the multi-domain EndoS and EndoS2, corynebacterial ENGases rely on a single GH18 domain, often paired with a unique short-loop or helix motif at their C termini.
Certain members, such as CM49 and CD51, feature additional domains, including a three-helix bundle (3HBD) and transmembrane helices, which hint at their evolutionary diversity and functional adaptations. For instance, CX35’s evolutionary proximity to EndoS and EndoS2 underscores its unique versatility among corynebacterial enzymes.
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CU43 has emerged as a frontrunner for clinical applications. Researchers tested this enzyme against various IgG-mediated pathologies using mouse models. The results were remarkable: CU43 outperformed existing treatments by a factor of 4,000, requiring significantly lower doses to achieve the same therapeutic effects. This potency could translate into fewer side effects and more versatile drug delivery options for patients.
“Human antibodies, although critically important for mounting an immune response, sometimes cause disease themselves,” explained Eric Sundberg, lead investigator and biochemistry researcher at Emory University. “The enzymes we discovered can modify antibodies in such a way that they no longer cause disease.”
This specificity is critical for conditions like MG, where overactive antibodies block communication between nerves and muscles, causing debilitating symptoms. By selectively targeting the problematic glycan on IgG, CU43 mitigates these effects without broadly suppressing the immune system.
Researchers also demonstrated CU43’s exceptional ability to hydrolyze complex-type (CT) N-glycans on IgG antibodies. Its specificity was confirmed through advanced liquid chromatography-mass spectrometry (LC-MS) analysis. Unlike some related enzymes, CU43 showed no activity on non-IgG substrates, highlighting its precision.
Even when tested against all classes of human antibodies, including IgA, IgD, IgE, and IgM, CU43 exhibited strict selectivity for IgG. This makes it a promising candidate for treating diseases that rely on IgG-mediated immune responses.
The implications of this discovery extend far beyond MG. IgG-mediated pathologies—from autoimmune hemolytic anemia to antibody-dependent enhancement in diseases like dengue fever—could potentially be addressed using these enzymes. The versatility of CU43 highlights its potential as a treatment for a wide array of immune-related conditions.
Dr. Jeffrey Ravetch, a collaborator on the study and immunologist at Rockefeller University, emphasized the significance of these findings: “The potency of this enzyme is quite remarkable when compared to current treatments for autoimmune diseases. It warrants further development for treating this important class of diseases.”
Importantly, CU43’s efficacy extends beyond symptom management. By directly modifying IgG antibodies, this enzyme offers a novel approach to addressing the root causes of IgG-mediated pathologies. Researchers envision its use in preventing and treating conditions ranging from immune thrombocytopenia to severe inflammatory diseases.
In addition to CU43, other corynebacterial ENGases, such as CP40 and CU43’s homologs, demonstrate promising features. For example, CP40 has been used successfully as a vaccine in sheep, providing protection against caseous lymphadenitis. These findings highlight the broader potential of corynebacterial ENGases in both therapeutic and preventive applications.
With its strong efficacy and targeted approach, CU43 is poised to enter clinical trials. Researchers are optimistic about its potential to transform the treatment landscape for autoimmune disorders and IgG-mediated diseases.
“We hope to leverage these promising results in mice to move this enzyme rapidly into clinical trials in humans,” Sundberg stated. “It could potentially be used to treat a wide range of autoimmune diseases and other IgG-mediated pathologies.”
The discovery of CU43 represents a milestone in therapeutic enzyme development. Its ability to selectively target disease-causing antibodies while sparing healthy immune functions underscores its transformative potential. As the scientific community continues to explore its applications, CU43 could become a cornerstone of precision medicine for immune-related disorders.
This discovery exemplifies how fundamental scientific research can pave the way for innovative therapies, offering new hope for patients suffering from challenging conditions.
By unraveling the mechanisms of IgG-specific ENGases, scientists have not only expanded our understanding of antibody biology but also opened new avenues for treating a host of diseases driven by immune dysfunction.
Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.
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