Summary: Researchers announced the successful completion of a Phase 1b clinical trial for a novel immunotherapy for Alzheimer’s disease. The trial evaluated IBC-Ab002, a humanized anti-PD-L1 monoclonal antibody specifically engineered to rejuvenate systemic immune responses rather than directly target neurotoxic amyloid beta plaques in the brain.
Key Facts
- Successful Safety Profile: The Phase 1b trial confirmed that IBC-Ab002 was safe and well-tolerated at all administered doses in patients with early-stage Alzheimer’s disease.
- Novel Non-Amyloid Paradigm: Instead of removing amyloid plaques directly, IBC-Ab002 targets the PD-1/PD-L1 inhibitory immune checkpoint to transiently unleash peripheral immune activity, which clears senescent cells and dampens brain inflammation.
- Reductions in Neurodegenerative Biomarkers: Biological evaluation confirmed that treatment reduced biomarkers of active neuronal injury and reversed markers associated with synaptic loss.
- Addressing Systemic Brain Aging: The therapy targets age-related immune exhaustion, operating on the principle that systemic immune decline is a primary driver of neurodegenerative disease progression.
- International Trial Scope: Clinical execution spanned 11 sites, including five centers in the United Kingdom, five in Israel, and one in the Netherlands.
Source: Weizmann Institute
Dozens of research teams around the world are working to halt, treat and even prevent Alzheimer’s disease, which silently develops in the brain for more than a decade before symptoms appear. Although recent years have brought important advances, researchers continue to search for therapies that can more effectively alter the course of Alzheimer’s and other forms of dementia.
Prof. Michal Schwartz of the Weizmann Institute of Science’s Brain Sciences Department has developed an innovative strategy for treating Alzheimer’s disease. A recipient of the Israel Prize in Life Sciences, Schwartz pioneered research showing that the body’s most protected organ – the brain – is tightly dependent on the immune system for its lifelong functioning, maintenance and repair.
These findings overturned the long-held dogma that the brain was entirely isolated from immune activity, and that any immune activity within the brain was inherently detrimental and should therefore be suppressed.
Schwartz also revealed the critical role of age-related immune dysfunction in driving the progression of brain aging. In particular, she proposed that, regardless of a neurodegenerative disease’s primary cause, age-related decline of the immune system fuels brain inflammation, a major driver of disease progression. This finding suggested that removing amyloid plaques, long considered a hallmark of Alzheimer’s, is not sufficient to halt the disease. Her discoveries opened a new path toward developing treatments for neurodegenerative diseases by targeting the immune system.
A Phase 1b clinical trial of an Alzheimer’s disease immunotherapy based on Schwartz’s work has recently been completed. The results of this first stage of clinical development – whose primary objective, as is standard for Phase 1 trials, was to evaluate safety – are reported today in Nature Medicine.
Beyond amyloid: the immune system
Instead of directly targeting Alzheimer’s amyloid plaque deposits, Schwartz’s team has focused on understanding how immune system dysfunction drives disease progression. This novel approach also reflects the growing recognition that Alzheimer’s disease is a systemic disorder, rather than solely a disease of the brain.
About a decade ago, using mouse models of Alzheimer’s disease and other forms of dementia, the team showed that transient, intermittent reduction of the suppression imposed on the immune system by inhibitory immune checkpoints, promotes the clearance of aging cells from the diseased brain, reduces brain inflammation and alleviates disease symptoms, slowing disease progression and improving memory.
The researchers focused on the PD-1/PD-L1 inhibitory checkpoint pathway as a target for treatment. Building on these discoveries, Schwartz co-founded ImmunoBrain, a company dedicated to translating her research into therapies for neurodegenerative diseases.
The company licensed the underlying technology and intellectual property from Yeda, the Weizmann Institute’s tech transfer company, and developed IBC-Ab002, a humanized anti-PD-L1 antibody specifically engineered to harness the newly discovered immune mechanism for the treatment of Alzheimer’s disease. Although IBC-Ab002 targets the same immune checkpoint molecule as anti-PD-L1 antibodies used in cancer immunotherapy, it has distinctive properties tailored for Alzheimer’s disease.
Following a series of successful studies in laboratory animals, a multicenter, international Phase 1 clinical trial enrolled 40 patients with early-stage Alzheimer’s disease at 11 medical centers: five in the United Kingdom, five in Israel and one in the Netherlands. The research was headed by Schwartz, while the clinical trial was led by Dr. Tommaso Croese, formerly a PhD student in Schwartz’s lab and now vice president of clinical development at ImmunoBrain, together with Prof. Catherine J. Mummery of the Dementia Research Centre at University College London.
The trial’s results showed that the treatment was safe and well tolerated at all tested doses, and that its biological activity matched its engineered design. The treatment, aimed at reversing immune aging, also reduced biomarkers of neuronal damage, as well as biomarkers associated with loss of synaptic function. These findings support further clinical development of this innovative therapeutic strategy.
Also participating in the study were Dr. Noa Bregman of Tel Aviv Sourasky University Medical Center (Ichilov) and Tel Aviv University; Dalia Bracha, Dr. Kuti Baruch, Dr. Alexander Kertser and Dr. Sharona Raveh of ImmunoBrain; and Dr. Eliezer Shochat.
“Aging is the greatest risk factor for Alzheimer’s disease,” Schwartz says. “Our research over the years has shown that one of the key contributors to disease progression is the aging of the immune system. Age-related decline in immune function fuels chronic inflammation in the brain, a major driver of the progression of Alzheimer’s disease and other neurodegenerative disorders.”
Schwartz concludes: “The goal of our biological therapy is to restore the immune system’s youthful capacity to protect the brain, thereby helping to arrest the disease or even reverse its course. We believe this approach could usher in a new era in the treatment of dementia and other neurodegenerative diseases, whose prevalence continues to rise as populations age and life expectancy increases.”
Funding: Prof. Michal Schwartz’s research is supported by the Sagol Institute for Longevity Research; the Thompson Family Foundation Alzheimer’s Disease Research Fund; and the Estate of Daisy Pinchas.
Key Questions Answered:
A: Traditional Alzheimer’s monoclonal antibodies target and bind directly to amyloid beta plaques inside the brain to promote their physical clearance. In contrast, IBC-Ab002 acts on the peripheral immune system outside the brain by blocking the PD-L1 checkpoint, restoring the immune system’s natural, youthful ability to combat systemic inflammation and clear damaging senescent cells.
A: As the immune system ages, it becomes overly suppressed through inhibitory checkpoint pathways like PD-1/PD-L1. This immune exhaustion prevents the body from resolving chronic neuroinflammation. Blocking PD-L1 briefly lifts these brakes, allowing systemic immune signaling to enter the central nervous system environment, reduce chronic inflammation, and support tissue maintenance.
A: In addition to meeting all primary safety endpoints, the trial showed that IBC-Ab002 demonstrated clear target engagement and reduced measurable fluid biomarkers associated with structural neuronal damage and synaptic degradation in early-stage Alzheimer’s patients.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Alzheimer’s disease research news
Author: Gizel Maimon
Source: Weizmann Institute
Contact: Gizel Maimon – Weizmann Institute
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Immunotherapy with a short-lived anti-PD-L1 antibody in Alzheimer’s disease: a phase 1b, randomized, double-blind trial” by Tommaso Croese, Catherine J. Mummery, Noa Bregman, Dalia Bracha, Kuti Baruch, Alexander Kertser, Sharona Raveh, Eliezer Shochat & Michal Schwartz. Nature Medicine
DOI:10.1038/s43856-026-01767-4
Abstract
Immunotherapy with a short-lived anti-PD-L1 antibody in Alzheimer’s disease: a phase 1b, randomized, double-blind trial
While Alzheimer’s disease (AD) is initiated by amyloid plaque accumulation, its progression involves local neuroinflammation that the brain cannot resolve when age-related dysfunction of the systemic immune system limits peripheral immune support.
Preclinical studies using rodent models showed that transient systemic blockade of programmed death-ligand 1 is associated with reduced neuroinflammation, neuroprotection and attenuation of disease progression. Based on the underlying mechanism, a new short-lived anti-programmed death-ligand 1 antibody with Fc-effector silencing and reduced FcRn binding (IBC-Ab002) was engineered.
Here, we report a randomized, double-blind, phase 1b first-in-human trial in early AD, with safety and tolerability as the primary endpoint. Forty participants were enrolled across five ascending dose cohorts (1–30 mg kg−1), with dosing administered four times at 3-month intervals.
Treatment was well tolerated, with no treatment-related serious adverse events or evidence of amyloid-related imaging abnormalities. Exploratory analyses at week 48 showed directional changes in cerebrospinal fluid biomarkers of neuronal and synaptic damage favoring the 30 mg kg−1 dose, although no doses reached statistical significance given the limited sample size.
The safety and tolerability profile supports further clinical development of systemic, intermittently administered IBC-Ab002 in early AD. ClinicalTrials.gov registration: NCT05551741.
