Q&A: CD6/ALCAM may hold key to more specific, effective therapies in lupus nephritis
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Uncovering a viable biomarker in a historically challenging disease like lupus nephritis is tantamount to striking gold if it can be used for one important purpose: Predicting treatment response.
And if that biomarker can be paired with an effective therapy? All the better.
Recent research has all but confirmed the ability of the CD6/activated leukocyte cell adhesion molecule pathway as a viable target in lupus nephritis, potentially shaving months off the time it takes to determine whether a patient is responding to therapy. Meanwhile, phase 1 results for itolizumab (Biocon) indicate that the drug may have the capacity to impact that target.
Chaim Putterman, MD, associate dean for research at the Azrieli Faculty of Medicine at Bar-Ilan University, in Israel, and professor in the division of rheumatology at the Albert Einstein College of Medicine and Montefiore Medical Center, in New York, and colleagues described T cells as “central” to the pathogenesis of lupus nephritis in patients with systemic lupus erythematosus.
“CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T-cell activation and trafficking,” they wrote.
Previous data have shown that soluble ALCAM may be elevated in the urine of patients with lupus nephritis, prompting the conclusion that this pathway is involved in development of the disease.
In their study, Putterman and his group assessed soluble ALCAM in the urine of 1,038 individuals with SLE and lupus nephritis. Importantly, the cohort was ethnically and racially diverse, according to the researchers.
They assessed both CD6 and ALCAM expression in kidney cells, and tested disease contribution through CD6 antibody blockade in murine models of SLE and acute glomerulonephritis.
Results showed a “resounding validation” of ALCAM in the urine as a biomarker that demonstrates renal activity in patients with SLE. These results were seen across ethnic and racial groups.
Although ALCAM expression was seen in renal structural cells, it was observed that CD6 was expressed exclusively in T cells. Both markers were elevated in kidney tissue from patients with lupus nephritis.
Moreover, blocking CD6 in models of spontaneous lupus and immune-complex glomerulonephritis yielded a significant improvement in several key parameters, including immune inflammatory markers and disease measures. The researchers concluded that the CD6/ALCAM pathway may be a viable disease biomarker and therapeutic target in lupus nephritis.
As for the drug, itolizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively targets CD6, a co-stimulatory receptor for ALCAM, that is expressed on the surface of autoreactive T cells, according to Putterman.
“It is associated with the pathology of a variety of autoimmune and inflammatory diseases,” he said.
Healio Rheumatology sat down with Putterman to discuss the need for both novel therapies and novel biomarkers in lupus nephritis, and what happens when this condition goes unchecked for too long.
Healio: How did you first arrive at the CD6/ALCAM pathway as a potential target for research?
Putterman: The initiative for studying this pathway came from one of our commercial partners. They had been studying CD6 in a number of other conditions, including graft vs. host disease and asthma, and were looking to expand into other potential indications. Because there are so many unmet needs in rheumatologic diseases, they came to me, asking what I thought may be a potential disease for drug development in our specialty.
Looking at the mechanism of CD6/ALCAM and the known importance of co-stimulatory pathways in the pathogenesis of SLE, I thought that lupus would be a potentially interesting area to focus on. T-cell proliferation, activation and migration into tissues, downstream effects of CD6/ALCAM signaling, are all immunologically relevant to pathways of disease in lupus. At the time, however, we did not have lupus specific support.
Healio: Was yours the only group that was interested in this pathway?
Putterman: Well, that is the really interesting part of this. In parallel, Dr. Chandra Mohan, at the University of Houston, was conducting biomarker studies. Independently, he found that the ligand of CD6 was present in the urine of lupus patients in high concentrations. He was just looking at this in an unbiased fashion to see what distinguishes the urine of lupus nephritis patients from lupus patients without nephritis and the general population. One of the highest expressed targets was ALCAM, which is the ligand for CD6.
Healio: Did you reach out to Dr. Mohan about this?
Putterman: The exact details of the “eureka” moment, if there was one, are a bit blurry, but Dr. Mohan and I have worked together for years on biomarker studies in lupus and lupus nephritis. I think what happened is that when we started thinking about CD6, I wanted to read more and educate myself on the subject. That is when I saw that Dr. Mohan’s group had already started to generate evidence for involvement of CD6/ALCAM interactions in lupus nephritis through his biomarker studies.
It occurred to me that this is another really good reason we should be considering lupus nephritis as a potential indication for a therapy that can modulate this pathway.
Healio: All of this seems to highlight the importance, and unmet need, of biomarkers in rheumatology in general, but also specifically in lupus and lupus nephritis.
Putterman: When we talk about unmet needs in lupus nephritis, we usually think about better and safer therapies. We know that despite treatment, a clinically significant proportion of patients will develop end-stage renal disease, or ESRD. ESRD is a therapeutic failure. It can occur due to poor patient compliance, but also, of course, because our therapies at this time are not effective enough.
Many patients have no response to first line therapies, or only a partial response. Furthermore, in lupus nephritis, there is a saying we like to use: Time is kidney. With the persistence of chronic inflammation in the kidney, even if the patient eventually responds, some of the tissue damage already incurred might not be reversible — which may also subsequently lead to further deterioration of kidney function in the future. So, we need to develop therapies to which patients will be respond to better and earlier.
Healio: Please discuss the highlights of the phase 1 trial of itolizumab. What would you say are the most significant findings that would be of interest to practicing rheumatologists?
Putterman: Itolizumab is currently being evaluated in patients with SLE and lupus nephritis as part of the EQUALISE trial, which is testing whether specifically blocking the CD6-ALCAM pathway can modulate the immune responses and ameliorate disease. The first portion of the study, which has been completed, was an open-label dose-escalation study in patients with active or inactive SLE, but without active proliferative lupus nephritis.
At completion, 35 patients were dosed subcutaneously at five different dosing levels — between 0.4 and 3.2 mg/kg times two doses — 14 days apart. The primary objective was to assess the safety and tolerability, with secondary objectives to assess pharmacokinetics and pharmacodynamics. Key findings were that itolizumab was well tolerated, particularly up to 2.4 mg/kg. Consistent with the mechanism of action of itolizumab, CD6 decreased significantly on CD4 cells and dose dependent increases in exposure were observed across the dose groups. Exploratory analyses showed reduction in proteinuria and albuminuria.
Given these data and the novel, targeted mechanism of the drug, the evidence supports continued evaluation of itolizumab in SLE/LN and other chronic autoimmune diseases.
Healio: The history of rheumatology drug development is filled with medications that perform well in phase 1 or 2, but then ultimately don’t make it to market. With this in mind, could you discuss the future of itolizumab?
Putterman: We have now shown, through a combination of previous work and our most recent publication, that soluble ALCAM is elevated in the urine of patients with lupus nephritis, the levels are associated with disease severity, and that the CD6-ALCAM pathway contributes to disease. Consequently, there is a distinctive opportunity here to treat lupus nephritis using targeted therapy paired with a biomarker to the CD6-ALCAM pathway.
Being able to identify patients that will respond to a particular therapeutic intervention could greatly improve treatment success rates. To that end, we are continuing our collaboration and working with the Accelerated Medicines Project to examine how levels of urinary CD6 and ALCAM in patients with lupus nephritis change over time, as well as their correlation with disease flares.
Further, we will be monitoring levels of urinary ALCAM in patients with lupus nephritis treated with itolizumab within the EQUALISE trial. This will allow us to better understand the efficacy of modulating the CD6-ALCAM pathway, the utility of the biomarker, and how this could potentially inform clinical practice.
In addition, given the unique first-in-class mechanism of itolizumab, it may eventually turn out to be complementary to other therapies. A combination of itolizumab as a T-cell modulator with B-cell directed therapies could turn out to be an effective and powerful treatment paradigm if modulation of both of these components of the immune system is needed.
Healio: Could you tie this back to biomarkers?
Putterman: Yes, it comes back to that unmet need. Let’s talk about how rheumatologists choose therapies for lupus nephritis. Most of us will go first to mycophenolate, and then cyclophosphamide as a second line and rituximab (Rituxan, Genentech) as a third line. But when should we be switching to a second line drug? If you take 100 patients with lupus nephritis in whom you initiate therapy, there will be a significant number that will not respond to mycophenolate, but you can only be sure of who is not responding after several months.
If we had a biomarker at baseline to tell us who will or will not respond we could treat them immediately with a different medication.
Healio: Are there any other uses of biomarkers?
Putterman: We could also use them to predict flares. The earlier you treat a flare, the better the patient will do.
Healio: Beyond these topics, is there anything else you would like to add?
Putterman: One more point that may be interesting pertains to the Accelerating Medicine Partnership project, or AMP. This is a large research partnership between the NIH and the pharmaceutical industry that started 6 or 7 years ago. The purpose was to accelerate development of new medications using cutting edge molecular biology tools for discovery. The technique chosen to identify new targets in SLE was single-cell RNA sequencing. The idea was to go to where the money is; let’s look at the affected tissue itself. This effort is continuing and generating a lot of excitement and novel findings.
Healio: How does this tie into the current research?
Putterman: AMP data helped encourage us to focus on CD6/ALCAM. As part of AMP, we analyzed this pathway, as I said, not only in the blood or urine, but also in renal tissue of lupus patients with active kidney disease having a biopsy for clinical indications. It was there that we found evidence that the CD6/ALCAM pathway was active. This evidence is not circumstantial. This is direct evidence from the inflamed organ and provided strong support that this pathway is a viable target worth looking at more closely.
Reference:
Chalmers SA, et al. J Clin Invest. 2022;doi:10.1172/JCI147334.
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Healio interview.
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