Designing Antibody-Based Therapeutics for Autoimmune Disorders
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Lupus is an autoimmune disorder where the immune system creates autoantibodies that react with self-molecules and can target various organs including the kidneys, brain and heart. As a result, lupus patients can suffer from chronic inflammation. One of the most common complications of lupus is lupus nephritis, where the inflammation caused by errant immune system activation in the kidneys prevents the removal of waste products and toxins.
Equillium has developed itolizumab, a first-in-class anti-CD6 monoclonal antibody therapy to prevent the pathogenesis of lupus. Cherie Ng, the senior director for research at Equillium, tells us more about how itolizumab works and the importance of targeting the CD6-ALCAM signaling pathway in lupus nephritis.
Katie Brighton (KB): Can you tell us a little about itolizumab’s mechanism of action against lupus nephritis (LN)?
Cherie Ng (CN): T cells play a central role in the pathogenesis of both systemic lupus erythematosus (SLE) and LN by mediating tissue damage and enhancing the production of autoantibodies via promotion of B cell differentiation, proliferation, and maturation. These T cells express CD6, a costimulatory receptor, that through its binding to activated leukocyte cell adhesion molecule (ALCAM) modulates both the activity and trafficking of effector T cells (Teff). The expression of both CD6 and ALCAM (CD6-ALCAM pathway) have been associated with pathogenic effector T cell activity and trafficking in multiple autoimmune and inflammatory diseases.
Itolizumab is an anti-CD6 monoclonal antibody. Our studies show that use of an anti-CD6 monoclonal antibody to block the CD6-ALCAM pathway in models of SLE and LN leads to prolonged survival, decreased infiltrating immune cells, lowered inflammatory cytokine levels and reduced renal pathology in a manner comparable to mycophenolate mofetil and cyclophosphamide, both potent immunosuppressors used in the treatment of LN. By specifically targeting CD6 on T cells, not only was there a decrease in T cell infiltration and activity but this led to decreased activity of other immune cell types, including inflammatory macrophages and neutrophils.
KB: Why did you choose to target the CD6 receptor over other T-cell receptors?
CN: The work in the paper stemmed from the observation made by Professor Chandra Mohan’s group that urinary ALCAM levels were significantly elevated in patients with LN. Based on a screen of more than 1100 urine proteins, soluble urinary ALCAM (uALCAM) was identified as one of the top molecules elevated in the urine of patients with SLE with active renal involvement compared with patients with quiescent or no prior nephritis. Because ALCAM is a ligand for CD6 and given the association of CD6 with pathogenic effector T cells, the next logical questions were: What is the source of the urinary ALCAM? Is the CD6-ALCAM pathway a driver of disease? Additionally, what makes CD6 such an interesting and unique target is that it is highly expressed on effector T cells but only lowly expressed on regulatory T cells, making it an ideal target for autoimmune and inflammatory diseases because it won’t inhibit the patient’s own mechanisms of controlling overactive T cell responses.
KB: Now signaling through the CD6-ALCAM pathway has been identified as having a pathogenic role in lupus, are you planning to investigate whether itolizumab can be used as a treatment strategy for other autoimmune conditions?
CN: Itolizumab has already demonstrated encouraging results in SLE patients without LN that had elevated urine protein/creatinine and albumin/creatinine ratios, where we saw a decrease in proteinuria. We anticipate announcing additional data for this indication later in 2022.
We are also conducting the Phase 1b study called EQUATE in acute graft-versus-host disease (aGVHD). Data presented at the recent American Society of Hematology meeting in December 2021 showed that treatment with itolizumab had a lasting, positive clinical impact on these patients. These patients also experienced a clinically meaningful reduction in steroid administration during the evaluation period.
KB: The study in JCI mentions using soluble urinary ALCAM as a biomarker for LN, do you think this has a potential clinical use as a diagnostic test?
CN: The JCI publication, for the first time, shows robust validation of urinary ALCAM as a biomarker. We found that urinary ALCAM can discern active renal involvement in SLE versus inactive, and show that there is no renal involvement, across a range of ethnicities. We believe these data support urinary ALCAM potentially being a clinical diagnostic.
KB: In the study, mouse models were used to test the CD6-specific monoclonal antibody (anti-CD6). The antibody treatment was administered close to the time disease is first detected in the animals. Does anti-CD6 still have an effect if administered later on, when the disease has progressed?
CN: We are looking into follow-up experiments blocking this pathway later in disease. In the paper, we tested two different models of LN: the MRL/lpr model which is a spontaneous model of lupus and LN, and the nephrotoxic serum nephritis model, an induced model that replicates glomerulonephritic events of LN. The timeline of disease in the nephrotoxic nephritis model is highly accelerated, with a decline in renal function within 24 hours so it is very difficult to test this model by treating later. Since we wanted to treat both disease models the same way, they were treated early in the disease process for the paper. Ultimately, the question of therapeutic efficacy will best be answered in human LN patients which is why we are conducting the clinical trial testing itolizumab in LN patients that is currently enrolling.
Cherie Ng was speaking to Katie Brighton, Scientific Copywriter for Technology Networks.