Antibody Therapeutic Candidate Reduces Immune Complexes Involved in Autoimmune Diseases

SYNT001, a monoclonal antibody, decreased immunoglobulin G (IgG) and IgG immune complexes in preclinical studies and a Phase 1 clinical study, with potential implications for treating autoimmune diseases

A broad variety of autoimmune diseases involve the development of pathogenic immunoglobulin G (IgG) antibodies which can attack cells and tissues and form immune complexes with the antigen to which they are directed. Immune complexes are particularly problematic as they can deposit in tissues and promote the further development of autoantibodies yet can only be removed or inhibited by invasive methods. A new study led by investigators at Brigham and Women’s Hospital in collaboration with Syntimmune Pharmaceuticals adds to the body of evidence that blocking the neonatal crystallizable fragment receptor (FcRn) has the potential to treat autoimmune diseases by removing not only IgG but also the immune complexes they form. In preclinical studies and a Phase 1 clinical study, the team presents evidence that expands the role of FcRn beyond simply removing IgG antibodies from the circulation, showing its potential for treating autoimmune diseases. The team’s findings are published in Science Advances.

“We anticipate that FcRn antibody therapeutics will be part of an important new class of drugs for the treatment of autoimmune diseases,” said corresponding author Richard Blumberg, MD, Vice Chair for Research in the Department of Medicine at Brigham and Women’s Hospital. “As these types of drugs move into the clinic, we need to pay attention to their effects on IgG immune complexes as that is something which has not received the attention it deserves.”

Previous studies have shown that blocking FcRn can lower levels of IgG in humans, the most common antibody found in the blood. IgG plays a critical role in fighting infection by binding pathogens such as viruses and bacteria but is also tied to autoimmune diseases such as lupus, pemphigus and more. IgG can also form complexes with antigens, which may further promote the autoimmune response, but the effect of blocking FcRn on the immune complexes had not been evaluated until now.

Blumberg and colleagues assessed the effects of SYNT001, an FcRn blocking monoclonal antibody, on IgG as well as IgG immune complexes in mice, non-human primates and humans. They found that SYNT001 decreased the levels of both IgG and IgG immune complexes in the circulation and inhibited the ability of the immune complexes to activate the immune system. The drug candidate was well tolerated in the Phase 1 study.

“The results of these studies suggest that FcRn blockade using SYNT001 has the potential to treat a variety of inflammatory and autoimmune conditions making it a promising therapeutic agent in reversing the effects of pathogenic IgG and IgG immune complexes,” the authors write.

Funding for this work was provided by Syntimmune, Inc., and by the National Institutes of Health (NIH DK53056). Multiple co-authors of this study were employees of Syntimmune, Inc., served as paid consultants to Syntimmune, Inc., or had equity interests in Syntimmune, Inc., a company developing therapeutic agents to target FcRn. Syntimmune, Inc., is now a wholly owned subsidiary of Alexion Pharmaceuticals, Inc., following its acquisition by Alexion in November 2018. A co-author is an employee of, and has equity interest in, Alexion Pharmaceuticals, Inc.

Paper cited: Blumberg, LJ et al. “Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses” Science Advances https://advances.sciencemag.org/content/5/12/eaax9586

 

New Way of Measuring White Blood Cell Function Offers Better Insights to Help Patients with Sepsis

Investigators develop advanced technology that can measure white blood cell activation and function, providing significantly more prognostic information about patients with sepsis

Caring for a patient with sepsis requires walking a treatment tightrope. Clinicians must identify the pathogen that is causing a patient’s infection, carefully monitor the patient’s response to antibiotics and supportive measures and race against the clock to prevent potential organ failure and death. Most of the time, physicians can control the infection itself. What ultimately leads to multi-organ system injury and fatality is the patient’s immune system’s over-exuberant response. Current testing and bedside diagnostics do not provide clinicians with precise and timely information needed to rapidly change their therapeutic approach.  To address this unmet need, investigators from Brigham and Women’s Hospital, in collaboration with colleagues at MIT, have developed a technology advance to enable measurement of the activation and function of white blood cells — the immune system’s sentinels — from a small aliquot of blood from patients with sepsis. The team’s new approach, results and clinical implications are detailed in a paper published in Nature Biomedical Engineering.

“Our idea was to develop a point-of-care diagnostic test that, instead of focusing on the white blood cell count, would inform us about white blood cell activation state and function,” said corresponding author Bruce Levy, MD, chief of the Division of Pulmonary and Critical Care Medicine at the Brigham. “It’s been exciting for us, as translational scientists, to work on a solution with outstanding bioengineer colleagues. Together, we’re able to address a truly important clinical problem.”

The team’s technological advancements are two-fold. The new approach uses microfluidics — tiny channels that aligns cells by their size, allowing investigators to sort out larger white blood cells from smaller red blood cells and other elements of the blood. This requires only microliter quantities of blood instead of milliliters — in other words, drops of blood instead of vials of it. This sample sparing approach, in turn, could reduce the risk of iatrogenic anemia among patients.

Secondly, working with the MIT team, the authors utilized a novel technology for measuring the electrical activity of cells, which changes when white blood cells are activated and can distinguish patients with and without inflammation, such as in sepsis. This electrical measurement — known as isodielectric separation — gave the team important information about the function and activation state of white blood cells.

The team assessed samples from 18 hospitalized patients and 10 healthy subjects, looking at the collected samples over the course of seven days. Both the activation state and function of white blood cells were significantly more predictive of the patient’s clinical course than were white blood cell counts.

The authors note that their findings may have implications beyond sepsis. Having a way to accurately and precisely measure the immune system’s response in microliter aliquots of blood could be useful in monitoring patients receiving immune modulating therapies, including treatment with immune checkpoint inhibitors for cancer or treatment with immunosuppressive drugs after an organ transplant. A more precise diagnostic test for the immune system’s activity would enable clinicians to adjust their immune modulating therapies to maximize benefit and minimize risk for individual patients.

“We’re excited to take the next steps forward,” said co-first author Bakr Jundi, MD, MMSc, a researcher in the Levy lab. “As physicians try to understand how sepsis affects patients and how we can better monitor patients, we hope this technology will help to address some of the main issues clinicians face.”

Funding for this work was provided by the National Institutes of Health (U24-AI118656, K08-HL130540, K12-HD047349).

Paper cited: Jundi, B et al. “Leukocyte function assessed via serial microliter sampling of peripheral blood from sepsis patients correlates with disease severity” Nature Biomedical Engineering DOI: 10.1038/s41551-019-0473-5

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