Robert Glanzman, MD, the chief medical officer at the ImmunoBrain Checkpoint, talked about IBC-Ab002 as a promising anti-PD-L1 monoclonal antibody to improve cognition in patients with Alzheimer disease.
IBC-Ab002 is designed to help the brain overcome the multiple pathological factors that contribute to cognitive decline in Alzheimer disease (AD), by activating the peripheral immune system. In preclinical studies using the therapy, transient activation of the peripheral immune system has reduced local brain inflammation and accumulation of toxic pathological proteins.1
In recent news, the company announced that it has dosed the first 2 patients in the randomized, double-blind, placebo-controlled, first-in-human phase 1b clinical trial (NCT05551741) investigating IBC-Ab002 in patients with early AD. The trial is being conducted in Israel, the United Kingdom, and the Netherlands, planning to enroll 40 participants. It also features single and multiple ascending doses, administered intravenously across up to 5 cohorts, with a 3:1 patient randomization for IBC-Ab002 or placebo. The therapy is typically administered once every 3 months and has a short exposure which allows for transient inhibition of the PD-L1 immune checkpoint pathway.
Robert Glanzman, MD, the chief medical officer at ImmunoBrain Checkpoint, sat down in an interview with NeurologyLive® to discuss the design of IBC-Ab002 for patients with AD. He talked about how the therapy activates the peripheral immune system for neuroprotection. Glanzman also provides supporting evidence for the cognitive improvement and reduction of harmful neuropathologies observed in animal models. In addition, the modifications introduced in IBC-Ab002 antibody design are projected to contribute to improved safety of the treatment.
Robert Glanzman, MD: IBC-Ab002 is a proprietary fully human anti-PD-L1 monoclonal antibody. PD-L1 and its receptor, PD-1, are immune checkpoint proteins found on the cell surface of immune cells; their interaction results in T cell immune suppression. IBC-Ab002 blocks PD-L1, thereby enabling immune cell activation. In cancer, this approach of targeting the PD-1/PD-L1 immune checkpoint pathway, has revolutionized therapy. For treating AD, we engineered IBC-Ab002 anti-PD-L1 antibody with unique characteristics, tailored for our proposed mechanism of action. As opposed to immunotherapy in oncology, in which prolonged exposure to the antibody is needed, IBC-Ab002 was designed for fast clearance from the circulation, which we characterized in preclinical study to be preferable for AD, in terms of both efficacy and safety.
What we're doing is activating the immune system in order to provide neuroprotection in AD. This is all based off more than 15 years of research at the Weizmann Institute by Professor Michal Schwartz, who recently won the Israel Prize, the Israeli equivalent of the Nobel Prize, for her scientific work. It’s very unique work, it’s cutting edge. We increasingly know that inflammation is what's driving progression in neurodegenerative diseases such as AD. By activating the peripheral immune system, we can ameliorate that. This has been shown in multiple animal models, where we show reduction in the neural pathology of AD, both in terms of amyloid beta deposition and tau deposition. We also show cognitive improvement in these animal models. It’s very exciting work. We're very excited about it. We're in phase 1 and we're moving forward.
There are several models that have been used. For example, the 5xFAD transgenic mouse model of amyloid pathology. It has shown remarkable results when you give the mouse anti-PD-L1 antibody both in terms of reducing amyloid pathology and also in terms of mitigating cognitive deficits, for which mice are tested by different cognitive tasks. We also used the same antibody in other mouse models of AD in which brain pathology is driven by tau and not amyloid. In these studies, we also observed significant reduction in brain tau pathology, and improved cognitive performance of the mice. That’s really driven again by activating the peripheral immune system.
We know that monocytes are a big part of that, both T cells and monocytes. We know that there are the microglia, which are the resident myeloid cells of the brain tissue. But there are also myeloid cells that can enter the brain from the blood circulation and get to sites of brain pathology. Once they get into the brain, it's hard to tell the difference sometimes between microglia and peripherally derived monocytes. We know that part of our mechanism of action with anti-PD-L1 is increasing recruitment of these blood monocytes into the brain.
Our plan for clinical development encompasses all indications for which we already have preclinical proof of concept. Accordingly, we plan to embark on future clinical trials in additional, more advanced, stages of AD, as well as other subtypes of AD such as familial AD. We are also working to advance clinical programs on tauopathies and additional neurodegenerative diseases.
We expect to see safety of the antibody, directional readouts on the mechanism of action, and central engagement, and generally the same data we have seen in the various mouse models.
Transcript edited for clarity.