Targeting BDCA2, neonatal Fc receptors ‘might not be a bad place to start’ in lupus
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Blood dendritic cell antigen 2 and neonatal fragment crystallizable receptor are two novel strategies in lupus that may play a larger role in the future, according to a presenter at the 2023 AWIR annual conference.
“Why on earth did she choose that?” Grace C. Wright, MD , PhD, president of the Association of Women in Rheumatology, said of her choice of topics for this early presentation at the conference.
One reason is that she described BDCA2 as an “emerging pathway” in lupus management, particularly cutaneous disease.
According to Wright, BDCA2 is exclusively expressed on plasmacytoid dendritic cells. When these cells produce too much interferon (IFN)-1, it contributes to the pathogenesis of SLE and other autoimmune conditions. Blocking BDCA2 could suppress downstream signaling of IFN-1, she added
“BDCA2 is very actively involved in early inflammatory processes,” Wright said. “If this is a plasmacytoid dendritic driver, this might not be a bad place to start.”
Phase 1 trials of litifilimab (BIIB059, Biogen), a humanized monoclonal antibody that binds to BDCA2, have demonstrated encouraging results in both cutaneous and other types of lupus, according to Wright, who noted improvements in both tender and swollen joint counts have been observed.
“Perhaps we do have a way to measure the impact of inhibiting these plasmacytoid dendritic cells,” she said.
Turning to neonatal Fc receptors, Wright noted that these therapies are not targeting cytokines, but the “recycling” that occurs to prevent degradation of IgG.
“The neonatal fragment crystallizable functions as a recycling mechanism to prevent degradation and extend the half-life of IgG and albumin in the circulation,” she said. “IgG is not just a carrier, but a participant in disease processes. Is it possible for us to adapt and adopt some of these principles so we can add this to our armamentarium?”
A number of neonatal Fc receptor inhibitors targeting this IgG recycling process are currently in development, Wright said. They accelerate the destruction of IgG and reduce the associated pathogenic processes without impacting IgA, IgM, IgE, the complement system or B cells, as the innate and adaptive immune systems mount a response.
Wright additionally cited results for efgartigimod (Vyvgart, Argenx), a human IgG1 antibody Fc fragment targeting pathogenic IgG autoantibody levels, in a cohort of patients with generalized myasthenia gravis. The drug has demonstrated encouraging efficacy results, with improved muscle weakness at 4 weeks, and was well tolerated, she said.
“We may be able to toy with this recycling pathway and impact the disease but not impact the ability of the host to mount a response,” Wright said.
However, she noted that there will be challenges as this approach is tested in other conditions.
“It is a complicated balance,” Wright said.
Meanwhile, advances in the general understanding of the innate and adaptive immune systems in the wake of the COVID-19 pandemic may bear fruit within the rheumatology space, including regarding the neonatal Fc receptor approach, according to Wright.
“The more we understand of immunology, the more we are able to draw that fine line and find a path forward,” she said.
Patience is critical as research continues, she added.
“If we can disrupt this IgG pathway, we can disrupt the inflammatory processes,” Wright concluded. “Maybe not for today, maybe not for tomorrow, but keep your eyes and ears open. This may become a useful adjunct for us.”
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Wright G. BDCA- 2 and FcRN Inhibitors: Emerging Pathways in Management of Immune Mediated Diseases Presented at: Association of Women in Rheumatology annual conference; Aug. 10-13, 2023; Orlando, Florida (hybrid meeting).
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