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Technique Converts Harmful Autoantibodies into Anti-Inflammatory Antibodies In Vivo

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A team of Massachusetts General Hospital (MGH) and Harvard Medical School investigators have found a way to engineer antibodies within an organism, converting autoantibodies that attack “self” tissues into anti-inflammatory antibodies in animal models of two autoimmune diseases.

The technology, developed in the laboratory of Robert Anthony, Ph.D., at the Center for Immunology and Inflammatory Diseases in the MGH Division of Rheumatology, Allergy & Immunology, involves administering enzymes that attach galactose and sialic acid to the “tail” portions of the detrimental immunoglobulin G (IgG), triggering anti-inflammatory activity.

“We were able to convert antibodies that cause autoimmune disease into anti-inflammatory antibodies by specifically modifying the sugars attached to the antibodies,” Dr. Anthony comments. “While more work is required, we hope that this approach of anti-inflammatory antibody conversion will have a beneficial effect on patients suffering from autoimmune and inflammatory diseases.”

Dr. Anthony, and co-researchers Jose D. Pagan and Maya Kitaoka, describe their technology in Cell, in a paper entitled “Engineered Sialylation of Pathogenic Antibodies In Vivo Attenuates Autoimmune Disease.”

Anti-Inflammatory Antibodies In Vivo.webp

IgG antibodies are a key player in the immune system and are essential for clearing pathogenic microbes by acting as a bridge between adaptive and innate immune system pathways, the authors explain. However, the body can also generate harmful IgG antibodies that attack self-tissues and so cause autoimmune disorders, including including systemic lupus erythematosus and rheumatoid arthritis.

IgG antibodies have also been harnessed for therapeutic use. Low doses of polyclonal intravenous immunoglobulin (IVIG) prepared from the antibodies of healthy donors can be given to patients who lack certain antibodies, while high-dose IVIG has been used for more than 40 years to treat inflammatory and autoimmune diseases by suppressing inflammation. Previous research has shown that the anti-inflammatory activity of high-dose IVIG is determined by glycan sugar molecules on the fragment crystallizable region, or Fc region (the tail-like portion of the Y-shaped antibody molecules), and this activity specifically requires sialylation of the glycan.

At present, as the pathogenesis of inflammatory and immunological diseases is unclear, there are few effective therapeutic drugs available in clinical practice. In such a context, the appropriate preclinical research techniques and models are required to help companies and researchers further develop and evaluate new drugs. Our Preclinical Pharmacodynamics Department has been deeply involved in this field for years, developing reliable animal-based efficacy evaluation models aimed at different targets and pathways, thus facilitating the clinical transformation of new drugs.

Glycans are normally attached to antibodies as the molecules pass through the cellular machinery that modifies protein molecules, but recent research indicates that glycans can also be modified extracellularly. This finding provided Dr. Anthony’s team with the starting point for engineering transferase enzymes that might be able to convert an inflammatory antibody to an anti-inflammatory antibody, in vivo, by modifying the Fc glycan.

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Attaching sialic acid to the Fc glycan requires another glycan, galactose, so Dr. Anthony’s team created two enzymes, B4Fc and ST6Fc, which mediate the attachment of galactose and sialic acid, respectively. When administered together, the enzymes triggered anti-inflammatory effects in a mouse model of rheumatoid arthritis and reduced kidney damage in a mouse model of lupus-related kidney inflammation. “When both enzymes were administered in a prophylactic or therapeutic fashion, autoimmune inflammation was markedly attenuated in vivo,” the authors write.

Further analyses indicated that the enzymes only affected the autoimmune antibodies at the site of inflammation, so there were no off-target effects. The team’s studies also showed that platelet activication was required for the anti-inflammatory effects, and that it was the activated platelets that donated the sialic acid and galactose.”Administration of this enzyme combination does not appear to affect sialylation of IgG in circulation or that of other glycoproteins in circulation,” the team states.”This is likely due to platelets’ release of galactose and sialic acid substrates only at sites of inflammation”

The technology developed by Dr. Anthony’s team could enable a more cost-effective approach to treating inflammatory and autoimmune conditions when compared with current IVIG therapy, which is expensive, in short supply, and also time-consuming to administer. “We found that our enzymes were effective at a 400-fold lower dose than high-dose IVIG, and by manipulating the enzymes already in an organism, our method eliminates the need for a lengthy IVIG infusion,” Dr. Anthony comments.

The ability to modulate IgG sialylation may also be exploited to help to improve the efficacy of vaccines, and also help to give clinicians control over the activity of IgG therapeutics, the authors suggest. “These results underscore the therapeutic potential of glycoengineering in vivo,” they conclude. “The potential for in vivo sialylation extends well beyond autoimmune and inflammatory conditions. Indeed, this approach may be applied to conditions currently treated by high-dose IVIG…. In vivo sialylation is a novel and potent approach to attenuate harmful autoantibody-mediated inflammation through glycoengineering endogenous antibodies and converting them to anti-inflammatory mediators.”

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