The next generation of rheum agents: Immunomodulation with neonatal Fc receptor targeting?
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Our cover story this month is on the next wave of immune-based therapies for patients with immune-mediated inflammatory conditions — and the prospects are bright.
I want to thank our faculty — Massimo Gadina, PhD, Jane Salmon, MD, Vibeke Strand, FACP, MACR, and Grace C. Wright, MD, PhD — and focus my comments on one aspect of this influx, namely the rise of immunomodulation. Our history of immune-based therapies dates back a mere 75 years or so, with the discovery and development of glucocorticoids. As we all know, the miracle-cure prospects for glucocorticoids were quickly dashed as we were rapidly confronted by the formidable array of short-term and long-term toxicities. As a result, we have been searching for better agents with enhanced efficacy and less toxicity.
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Now consider, among all the immunotherapeutic agents we possess in our armamentarium, the options that we generally gravitate to in settings where we are trying our hardest to avoid infectious complications. Next consider what we generally gravitate to for many disorders of unclear immunopathogenic mechanisms but with strong evidence of autoimmunity. In my mind, both intravenous immunoglobulin (IVIG) and plasma exchange (PLEX) are high on this list. We all recognize that, in general, although widely used as empiric therapies, these modalities are limited by a paucity of clear evidence of effectiveness, with limited availability and great cost.
So now we are stepping carefully into the next generation of therapies, some of which appear to be equally or even more immunomodulatory than current agents. Among these, I choose to focus on the emerging array of inhibitors of the neonatal Fc receptor. I and others discuss these agents in our roundtable, and I highly recommend the narrative review cited below if you are looking for a deeper dive.
For now, I am excited for several reasons regarding this therapeutic class despite their status of being approved for only a single indication in myasthenia gravis. A quick look at the current scope of clinical trials of agents in this class on Clinicaltrials.gov reveals a remarkable array of active studies in a remarkably diverse group of disorders, including Sjogren’s syndrome, rheumatoid arthritis, postural orthostatic tachycardia syndrome (POTS), long COVID, fibromyalgia, autoimmune mediated anemias and others. On the plus side, at least theoretically, agents in this class may potentially be effective in any disorder in which autoantibodies are suspected to be playing a pivotal role, even if their precise identification remains elusive.
For now, that is quite an attractive property and, at the moment, the toxicity profile appears modest with apparent preservation of humoral memory. What if we ultimately achieve one or more therapeutics that potentially mirrors many of the attractive attributes of IVIG, but are not resource-limited and possibly more cost effective? However, as with investing, past performance is no guarantee of future returns. The next few years may provide us with a strong immunomodulatory therapeutic option for an array of diseases that are orphan in terms of effective treatments — or they may not. Let us conclude with one of my favorite sayings: “The data will be the data.” That is my take, please share yours with me at calabrl@ccf.org or at rheumatology@healio.com.
- Reference:
- Pyzik M. Nat Rev Rheum. 2023;doi:10.1038/s41577-022-00821-1.
- For more information:
- Leonard H. Calabrese, DO, is the Chief Medical Editor, Healio Rheumatology, and Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic.
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