NeuroVoices: Tanuja Chitnis, MD, on Targeting Anti-CD3, Other Biomarkers in Progressive Multiple Sclerosis

Tanuja Chitnis, MD

Despite the advancement of therapeutics for patients with relapsing forms of multiple sclerosis (MS), the progressive patient population has seen only a few drug development successes. Under the approval of an investigational new drug application, a team of investigators, led by Tanuja Chitnis, MD, evaluated the therapeutic effect of foralumab in a singular patient with secondary progressive MS. In a phase 1 study, foralumab, a nasally administered anti-CD3 monoclonal antibody, was found to be safe with immune effects seen at the 50-ug dose.

The case-study, presented at the 2022 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, June 1-4, in National Harbor, Maryland, featured a 61-year-old man with nonactive secondary progressive MS for over 20 years who was still progressing despite treatment with anti-CD20 ocrelizumab (Ocrevus; Genentech) for 2 years. Foralumab was initiated in May 2021, and the patient continued on it for 6 months with a 7-week washout period after 3 months. The agent was administered at 50 ug 3 times weekly, for 2 weeks with a 1-week rest period following that.

Over a 6-month treatment period, the patient demonstrated reduced microglial activation on [F-18]PBR06 PET imaging, decreased levels of proinflammatory cytokines, and had positive clinical effects. Chitnis, associate neurologist, Brigham and Women’s Hospital, and professor of neurology, Harvard Medical School, sat down for a new iteration of NeuroVoices to discuss anti-CD3 therapy and the events leading up to this case study. She provided insight on the prominent biomarkers being discussed for progressive MS and how these positive findings may be replicated.

NeurologyLive^®: What previously led you to believe that an anti-CD3 agent such as foralumab could have potential in MS?

Tanuja Chitnis, MD: The background to this study is that anti-CD3 given nasally was first tested in animal models of [experimental autoimmune encephalomyelitis] of multiple sclerosis by Mayo et al that were published in Brain in 2016.2 They showed that this reduced microglial activation, as well as astrocyte inflammation, in the brains of these models, reduced progressive disease. That was the basis of why we thought anti-CD3 would work. I completed a phase 1 study about 2 years ago where we tested 3 different doses of foralumab, which is a human anti-CD3 antibody. We tested the 3 doses, and they were found to be safe in health controls, so we decided to move to patients with secondary progressive multiple sclerosis.

This is where the need really is. We were able to recruit a patient who had inactive secondary progressive MS under an expanded access protocol that was approved by the FDA. We gave him foralumab 3 times a week for a period of 2 weeks, and then one week of rest, which constitutes a 3-week cycle of treatment. We gave the cycles of treatment for 6 months in total, with some breaks in between. We were able to show that it reduced microglial activation on PET imaging using the F-18 PBR06 ligand, which attaches to, or targets the TFPO molecule and is present on astrocytes and microglia in the central nervous system.

We showed a reduction of this PET signal of activated microglia after 3 months of treatment, and at 6 months of treatment. This was across different areas of the brain and was in collaboration with Tarun Singhal, MD, MBBS, who is also at the Brigham and Women’s Hospital. We also looked at inflammatory biomarkers in the blood using a sensitive proteomic assay. We evaluated different cytokines and found that foralumab treatment in this patient reduced IL-6 levels—IL-1 beta and IL-18 levels. Additionally, I think it’s important to note that safety wise, the patient has been doing very well. There have been no issues on treatment, he has tolerated the treatment well, no adverse events, and we’ve been monitoring his laboratory tests carefully. We’ve been doing your nose and throat evaluations every 3 weeks and those have all been normal. That’s heartening. The patient feels stable and somewhat improved, and we’ve seen that his motor scores, his pyramidal scores, have improved on treatments. We’re encouraged by that. He’s received 6 months of treatment now and is doing well.

Are there certain biomarkers that are specific only to progressive MS?

We’re getting a clearer picture of what is driving disease progression and its largely by innate immunity within the brain and [central nervous system] in general. We’re now seeing, and several groups have shown, that progressive MS is associated with activated microglia on PET imaging and there are different ligands that have been studied and used. Our group, and some of my work specifically, has focused on blood biomarkers. We’re looking at the glial fibrillary acidic protein, or GFAP, in the serum, and this has been associated with both progressive disease and disease progression, and maybe even a predictor of progression. That’s something that has been elicited by astrocytes which of course play a major role in disease progression. We’re following up on that biomarker as well as other serum biomarkers that reflect astrocytic and microglial activation.

How can we expand on these findings?

We have started treating a second patient, and he’s been tolerating the treatment very well. We’re in the process of assessing similar biomarkers in this patient. We also received approval to evaluate another 8 patients under an expanded access program, and we’re hoping to start that this summer and be able to offer the drug to an additional group.

If successful, is targeting anti-CD3 something that companies will look to exploit?

Part of it is that anti-CD3 is probably an important molecule and target, but the other real novel aspect is the nasal delivery. That is just starting to be discovered in neurological diseases and it’s been one of our challenges to get these drugs across the blood brain barrier. From our studies, at least in animal models, the drug accumulates in the cervical lymph nodes and probably has an effect throughout the brain through the glymphatic and through regulatory molecules and cells that then get into the brain. I think this approach of nasally delivered treatments might be the future for both progressive MS as well as other neurological diseases.

Transcript was edited for clarity. Click here for more coverage of CMSC 2022.

REFERENCE
1. Chitnis T, Singhal T, Zurawski J, et al. Nasal anti-CD3 monoclonal antibody (foralumab) reduces PET microglial activation and blood inflammatory biomarkers in a patient with non-active secondary progressive MS. Presented at: CMSC Annual Meeting, 2022; June 1-4; National Harbor, MD. LB
2. Mayo L, Da Cunha AP, Madi A, et al. IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation. Brain. 2016;139(Pt 7):1939-57. doi:10.1093/brain/aww113