Autoimmune Immunotherapy Is Shifting Upstream: AnaptysBio on Targeting Pathogenic Immune Cells
By: Soumya Shashikumar, MBiotech
Interviewee: Paul F. Lizzul, MD, PhD, MPH, MBA, Chief Medical Officer, AnaptysBio
Autoimmune Immunotherapy Is Shifting Upstream: AnaptysBio on Targeting Pathogenic Immune Cells
By: Soumya Shashikumar, MBiotech
Interviewee: Paul F. Lizzul, MD, PhD, MPH, MBA, Chief Medical Officer, AnaptysBio
Autoimmune drug development is moving beyond single-cytokine blockade toward targeting pathogenic immune cells that drive disease.
Despite major treatment advances in immunology, many patients with autoimmune and inflammatory diseases continue to experience incomplete or short-lived responses, often cycling through multiple therapies without achieving sustained control.
Conditions such as rheumatoid arthritis (RA), ulcerative colitis (UC), atopic dermatitis and celiac disease remain marked by heterogeneous biology, variable treatment responses and, in some cases, a lack of approved pharmacologic options.
Building on these shifts in the field, Paul F. Lizzul, MD, PhD, MPH, MBA, Chief Medical Officer of AnaptysBio, shared his perspective on how deeper insight into immune-cell biology is reshaping therapeutic strategy, with the aim of achieving more durable control beyond short-term suppression of inflammation.
A board-certified dermatologist with academic and regulatory experience, Dr. Lizzul has led clinical and translational programs across multiple inflammatory diseases, including roles in global development and service on the FDA’s Dermatology and Ophthalmic Drugs Advisory Committee.
In a recent Xtalks Clinical Edge interview, Dr. Lizzul drew on examples from ongoing Phase I and Phase II studies across autoimmune indications, including celiac disease, RA and UC, to illustrate how cell-targeted strategies are being evaluated in the clinic.
From Cytokines to the Cells That Drive Disease
Dr. Lizzul described a fundamental evolution in how immunology drug development is being approached.
“Historically, development organizations typically targeted single cytokines,” he said. “That is evolving over time to more directly try to target these cells that are secreting and driving inflammation with these cytokines.”
Rather than focusing on one inflammatory messenger at a time, the field is increasingly moving upstream, toward the immune cell populations that initiate and sustain tissue injury. This shift is being driven by a growing understanding of how different immune compartments interact and which cell types sit at key control points in disease.
Celiac disease illustrates this concept particularly clearly. In response to gluten exposure, CD4 helper T cells in the gut recognize gluten-derived antigens and release cytokines, including IL-2. These signals activate downstream CD8 cytotoxic T cells, known as intraepithelial lymphocytes, which infiltrate the intestinal epithelium and directly mediate tissue damage.
Dr. Lizzul explained that one emerging strategy is to intervene at receptors shared across both of these pathogenic populations, rather than focusing on a single downstream cytokine. CD122, a component of the IL-2 and IL-15 receptor complex, is expressed on both CD4 helper T cells and CD8 cytotoxic T cells, placing it at a convergence point in the inflammatory cascade.
Some approaches in the field have focused primarily on IL-15 and its effects on cytotoxic T cells. In contrast, targeting CD122 offers the potential to modulate both upstream helper cells that recognize antigens and downstream effector cells that execute tissue injury, thereby addressing a broader portion of the disease-driving network.
Persistent Unmet Need in Chronic and Refractory Disease
Although therapeutic options have expanded in diseases such as RA and UC, many patients continue to experience inadequate or waning responses.
“Many of these [inflammatory and autoimmune] diseases are chronic diseases, so they require lifelong treatment,” Dr. Lizzul said. “So you really want to approach this from the perspective of developing treatments that can offer durable efficacy over time with the hopes that patients may not have to take medicines forever on a daily basis and hopefully can extend a duration between when they have to take medicines to treat their specific disease.”
Beyond controlling symptoms, a central objective is to achieve durable benefit and, ultimately, remission. Even in indications with multiple approved agents, a substantial proportion of patients become refractory over time and must move from one therapy to the next.
“There is still an unmet need, even in areas where people may believe that there’s quite a number of therapeutic options available, patients are still not necessarily doing well,” highlighted Dr. Lizzul.
At the same time, celiac disease remains an area with no approved pharmacologic treatments. While strict gluten avoidance is the cornerstone of management, complete elimination is difficult in daily life, and inadvertent exposure is common, allowing immune activation and intestinal injury to persist.
“There is still an unmet need, even in areas where people may believe that there’s quite a number of therapeutic options available, patients are still not necessarily doing well.”
— Paul F. Lizzul, MD, PhD, MPH, MBA, Chief Medical Officer, AnaptysBio
“There is still an unmet need, even in areas where people may believe that there’s quite a number of therapeutic options available, patients are still not necessarily doing well.”
— Paul F. Lizzul, MD, PhD, MPH, MBA, Chief Medical Officer, AnaptysBio
Designing Rigorous Trials in Heterogeneous Populations
Autoimmune studies routinely enroll patients with diverse disease histories, prior treatment exposure and levels of tissue damage, making trial design and interpretation particularly challenging. Dr. Lizzul emphasized that addressing this complexity starts with incorporating the patient perspective early in development.
“From a non-clinical or scientific perspective that’s more patient-focused, it’s really about getting feedback from patients as you undergo the process of developing a protocol and thinking about how you’re going to measure their disease activity,” he said.
Beyond patient input, he described the importance of ensuring that results were obtained methodologically across varied backgrounds. This includes examining outcomes in subgroups defined by prior treatment exposure, such as patients who are naïve to advanced therapies versus those who have cycled through multiple mechanisms of action, to assess whether responses differ across these populations.
There is also value in evaluating multiple, independently assessed endpoints rather than relying on a single measure, using centralized laboratories and validated biomarkers to improve analytical consistency and appropriately sizing studies to reduce variability.
“When studies are very small, sometimes it can be challenging, and that does introduce variability into the data, but as you design more robust and larger trials, that helps to address that particular aspect of challenge,” he added.
Probing Durability and Tissue Healing
Assessing long-term benefit is particularly challenging in diseases marked by fluctuating activity and structural tissue damage.
Dr. Lizzul referred to their Phase Ib study in celiac disease, where a two-cohort design is being used to explore both prevention of injury and tissue healing. One undergoes a controlled gluten challenge to assess whether treatment can prevent the development of mucosal injury, measured by villus height-to-crypt-depth ratios. The other reflects real-world patients who already have intestinal damage from inadvertent gluten exposure, allowing investigators to assess whether blocking key immune pathways can support healing of existing lesions.
In RA, Dr. Lizzul pointed to findings from a Phase IIb clinical study in which patients were followed after treatment discontinuation. He noted that clinical improvement persisted for several months after dosing stopped.
“We saw very good Phase II results, but what was most interesting there is that those patients continue to get better over time as they are dosed. What was even more impressive is once the therapy was stopped and we followed those patients for three months off of drug, they continued to do well,” he explained.
Dr. Lizzul noted that such observations help address a critical question in autoimmune development: not only whether a therapy improves symptoms, but whether it can shift the immune system toward a more stable, long-lasting and balanced state.
“From a non-clinical or scientific perspective that’s more patient-focused, it’s really about getting feedback from patients as you undergo the process of developing a protocol and thinking about how you’re going to measure their disease activity.”
— Paul F. Lizzul, MD, PhD, MPH, MBA, Chief Medical Officer, AnaptysBio
“From a non-clinical or scientific perspective that’s more patient-focused, it’s really about getting feedback from patients as you undergo the process of developing a protocol and thinking about how you’re going to measure their disease activity.”
— Paul F. Lizzul, MD, PhD, MPH, MBA, Chief Medical Officer, AnaptysBio
A Portfolio Built Around Cell-Selective Immunomodulation
Across its pipeline, AnaptysBio is applying a consistent strategy of engineering monoclonal antibodies to selectively modulate immune cells central to disease biology.
“We’re really trying to target those pathogenic cells that are key drivers of disease,” noted Dr. Lizzul.
In Phase II studies in rheumatoid arthritis and in a separate Phase II study in UC, this approach has focused on pathogenic T cells enriched not only in the circulation but also within inflamed tissue. In RA, he noted that these cells are highly expressed in the synovium, and that their reduction at the site of disease provided a direct link between molecular mechanism and clinical response.
In celiac disease, development efforts are centered on antagonizing CD122 to modulate both upstream CD4 helper T cells that recognize gluten and downstream CD8 cytotoxic intraepithelial lymphocytes that mediate epithelial injury. The company will initiate a second cohort of ANB033’s Phase 1b study to include eosinophilic esophagitis (EoE) in Q1 2026. An earlier-stage program targets plasmacytoid dendritic cells through modulation of BDCA2 and is being evaluated in a Phase I study.
Restoring Immune Balance and Looking Ahead
Looking to the next decade, Dr. Lizzul expects continued innovation in how autoimmune and inflammatory diseases are approached, driven by a deeper understanding of immune-cell biology and how dysregulated pathways can be more precisely corrected.
“One concept is getting patients towards immune balance or homeostasis rather than just continuing to treat inflammation,” he said. “Trying to get their immune system back to a normal level of stasis where it was before they were having dysregulation that was driving their particular disease.”
He noted that advances in cell-based approaches are likely to play an increasing role in immunology, as understanding of immune cell function and manipulation continues to evolve.
“I think we’ll continue to see a desire to shift towards personalized immunotherapy, so treatments that are more targeted towards a specific individual and what’s driving their particular disease rather than just a population approach.”
ABOUT Paul F. Lizzul
Paul leads the company’s development organization, including clinical medicine, clinical operations, regulatory affairs, pharmacology and toxicology functions. Prior to Anaptys, he has served as Global Development Lead for Inflammation at Amgen, Chief Medical Officer of Sienna Biopharmaceuticals and Senior Medical Director at Kythera Biopharmaceuticals.
Paul served as Assistant Professor of Dermatology and conducted clinical research at Tufts Medical Center. He is a board-certified dermatologist, a faculty member of the American Academy of Dermatology and has served on the United States Food and Drug Administration (FDA) Dermatology and Ophthalmic Drugs Advisory Committee. Paul received his MD, PhD in Molecular Genetics and MPH in Epidemiology from the Robert Wood Johnson Medical School at Rutgers. He has also earned an MBA in entrepreneurship from the Rutgers Business School.