Therapeutic antibodies in the fight against Alzheimer’s

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ImmunoBrain Checkpoint (IBC) is currently dosing patients in a clinical trial with its monoclonal antibody for Alzheimer’s disease (AD). DDW’s Megan Thomas caught up with Professor Michal Schwartz to learn more about her work and the work being carried out by IBC.

MT: Can you provide an overview of your career to date in the field of therapeutic antibodies, and its importance in the field of neuroimmunology?

MS: My career has been defined by my work in the field of neuroimmunology in which I have sought to define the nature and extent of interactions between the brain and the peripheral immune system. My introduction to the field of therapeutic antibodies came about as an extension of this work, leading to my desire to find a way to translate preclinical findings into a therapeutic modality for treating neurological disease.

MT: Can you provide an overview of the work being carried out at IBC?

MS: We are currently dosing patients in a Phase I clinical trial to evaluate our lead asset, IBC- Ab002, for safety, tolerability, and pharmacokinetics in patients with early-onset AD. IBC-Ab002 is a monoclonal antibody targeting the immune checkpoint protein PD-L1, a target most notably used in the field of immuno-oncology. Our preclinical findings have indicated that targeting PD-L1 is an effective strategy for leveraging the immune system to treat neurodegeneration.

MT: IBC describes itself as using outside the box thinking to reimagine the way we treat AD. Can you elaborate on what ‘inside’ the box thinking is in this scenario and how the work IBC is doing differs?

MS: Traditionally, the approach to treating AD has primarily relied on targeting neurotoxic proteins such as amyloid beta and tau within the brain. Yet, it is widely accepted now, that additional processes within the brain contribute to cognitive loss and should be contained, such as local brain inflammation. Our approach is to leverage the power of the immune system to help clear the toxic proteins as well as to arrest the local brain inflammation through endogenous mechanisms. By rejuvenating the immune system, a natural process within the body, our approach seeks to restore overall ability of the brain to fight the disease instead of directly targeting specific hallmarks of the pathology.

MT: If successful, what will IBC’s clinical trial mean for the treatment of AD?

MS: This would represent a whole new paradigm, not just in terms of understanding and treating AD, but in addressing other neurodegenerative diseases as well. There is the potential, through a deeper comprehension of the immune system’s communication with the brain, to consider immunotherapy as a preventative approach for delaying the onset of AD symptoms.

MT: Why is there a gap between neuroimmunology research and clinical practice, and what can be done to bridge it?

MS: The field of neuroimmunology has experienced significant progress in recent years, but there is still so much yet to be discovered. The pursuit and validation of science takes time and requires effort and investment from all parts of the scientific community. We believe that in this field there is a wide gap between the progress and understanding of the various mechanisms in academia and the adoption of these novel pathways by pharmaceutical R&D teams. The best path forward is to continue to expand upon the body of preclinical research in the field, while prioritising pivotal findings for validation in humans. This is exactly what we are doing by targeting the PD-L1 immune checkpoint in our first human studies.

MT: What are other challenges faced when it comes to developing monoclonal antibodies for neuroimmunology?

MS: It is imperative to understand the mechanism of action, specifically to discern whether the primary target of the antibody resides within the brain or in the periphery. Furthermore, a comprehensive characterisation of its pharmacodynamic properties is essential to maximise its effectiveness.

In our case, based on robust preclinical studies, IBC understood that its optimal activity in neurodegenerative diseases could be achieved by an antibody with distinctive features than those used in oncology. Therefore, IBC tailored its own proprietary antibody to its mechanism. This also happened to coincide with advantages with respect to its safety profile.

MT: Where are the opportunities in 2024 for this field? What about beyond that, looking ahead 10 years?

MS: There are a lot of reasons for optimism in the field of neurodegenerative disease research. In 2024, we look forward to our interim data readout with initial single- and multiple-ascending dose data from our clinical trial of IBC-Ab002.

Over the next 10 years, we believe additional members of the scientific community will research the connection between the peripheral immune system and the brain to provide a better understanding of these interactions across a number of different disease states. One of the most exciting aspects of this field is for the study of ageing as a whole, and how we can utilise the immune system to maintain a healthy brain during ageing.

MT: How does harnessing the power of the immune system to target neurological disorders compare and contrast to other treatment modalities in this field? Why is this the avenue you have dedicated your work to?

MS: The most significant advantage of our approach lies on a profound and emerging understanding of AD and specifically on the breakthrough understanding of the key role of the immune system on brain maintenance that is lost in ageing, a major risk factor in AD manifestation. Our approach is centred on the restoration of the immune system’s capacity to support the brain, which unlike other treatment modalities, indirectly and simultaneously addresses multiple factors within the brain that contribute to the escalation of the disease.

In essence, we harness the natural capabilities of the immune system, which, under disease conditions, are compromised (not necessarily as the primary cause, but as a key contributing factor). My enduring fascination with the intricate interactions between the brain and the immune system has driven my unwavering dedication to this field of study.

DDW Volume 25 – Issue 1, Winter 2023/2024 – Therapeutic Antibodies Guide

Professor Michal SchwartzBiography

Professor Michal Schwartz is a prominent scientist at the Weizmann Institute of Science, and a pioneer in the field of neuroimmunology. She won the 2023 Israel Prize in Life Sciences and co-founded a biotech company based on her research called ImmunoBrain Checkpoint (IBC), where she serves as its Chief Scientific Officer.

 

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