Our science

From overturning the old dogma to a new therapeutic approach for neurodegeneration

Anti-PD-L1 mechanism of action

Transient anti-PD-L1 checkpoint blockade briefly releases the brake on peripheral T-cell activity, initiating an immune repair cascade rather than continuous immune activation (Rosenzweig et al., 2019). Monocytes and regulatory T cells (Tregs) are recruited, and monocyte-derived macrophages reach the CNS, where preclinical studies show reduced neuroinflammation and synaptic and neuronal protection (Rosenzweig et al., 2019; Ben-Yehuda et al., 2021). Clearance of senescent microglia following anti-PD-L1 treatment is described in the supplied preclinical scientific deck (Immunobrain, October 2026). In the mouse models studied, anti-PD-L1 treatment also improved cognition, including learning and memory, and disease-relevant behavioural outcomes where assessed (Rosenzweig et al., 2019; Dvir-Szternfeld et al., 2022). These preclinical findings do not establish improvement in cognition or clinical symptoms in patients. This repair response is macrophage-dependent, requires CCR2-dependent monocyte recruitment, and can operate independently of TREM2 (Ben-Yehuda et al., 2021; Dvir-Szternfeld et al., 2022). The antibody initiates the response outside the brain; recruited immune cells carry out the repair (Rosenzweig et al., 2019; Dvir-Szternfeld et al., 2022). IBC-Ab002 is engineered around this biology for transient, controlled peripheral immune activation (Immunobrain corporate scientific deck, October 2026).

Sources: Rosenzweig et al., Nature Communications, 2019; Ben-Yehuda et al., Molecular Neurodegeneration, 2021; Dvir-Szternfeld et al., Nature Aging, 2022; Immunobrain corporate scientific deck, October 2026.

01 | Scientific foundation

Prof. Michal Schwartz challenged the old dogma

The brain was long viewed as largely immune-isolated. Her research helped establish a fundamentally different paradigm: the brain depends on regulated support from the peripheral immune system for maintenance, resilience and repair.

From the brain immune privilege to privileged immunity of the brain

Old dogma

The brain is completely isolated from the immune system

  1. Lymphatic-like vessels in meninges (ignored)
    1787
  2. The brain is physically isolated
    Blood-Brain-Barrier
    1885
  3. The brain is functionally isolated
    Immune privilege
    1948

Contemporary understanding

The brain is NOT isolated from the immune system

  1. Peripheral immune cells (protective autoimmunity; T cell and monocyte-derived macrophages) support CNS repair
    1998/1999
  2. Brain functional plasticity is tightly dependent on the immune system
    2004/2006
  3. Meningeal and blood-cerebrospinal barriers serve as immunological niches and gateways
    2013
  4. The brain is equipped with structural and functional lymphatic system
    2015

This discovery is the scientific foundation of Immunobrain. Rather than treating peripheral immunity as a threat to be excluded from the CNS, our approach is built on restoring a physiological brain-immune dialogue that becomes impaired with aging and neurodegenerative disease.

Sources: Schwartz laboratory body of work; Castellani, Croese, Peralta Ramos & Schwartz, Science, 2023; Schwartz et al., Neuron, 2022.

02 | Brain-immune ecosystem

The brain relies on peripheral immunity

Peripheral immune cells support brain maintenance remotely and can be recruited through specialized CNS interfaces when repair is needed.

The key implication is that brain repair is not performed by resident cells alone. CNS borders, meninges and the choroid plexus provide regulated routes for immune communication and selective recruitment of protective peripheral cells.

Sources: Croese, Castellani & Schwartz, Nature Immunology, 2021; Castellani et al., Science, 2023.

03 | What changes with aging

Aging disrupts both sides of the system

Neurodegeneration develops in the setting of chronic brain inflammation and declining peripheral immune competence.

With aging, microglia can acquire dysfunctional and senescent states while peripheral immunity becomes less capable of mounting an effective repair response. The result is a failure to resolve inflammation, increasing vulnerability of synapses and neurons.

Sources: Immunobrain scientific deck; Baruch, Deczkowska et al., Science, 2014; Deczkowska et al., Nature Communications, 2017.

Alzheimer's disease progression is driven by neuroinflammation and systemic immune aging

Peripheral immune aging
Ageing
Neuroinflammation / microglial dysfunction
Neuronal / synaptic damage
Cognitive decline
Amyloid accumulation & tau pathology

Immunobrain

Rejuvenation of the immune system renews brain-immune dialogue, facilitates the homing of immune-repairing cells that clear senescent microglia, and resolves inflammation. It can rescue dysfunctional neurons, providing neuroprotection.

04 | Why peripheral macrophages matter

Resident microglia and recruited macrophages are not redundant

A central insight from the Schwartz laboratory is that resident microglia alone may be insufficient for repair under pathological conditions.

Peripheral macrophages are required for CNS repair
Recruited macrophages show distinct anti-inflammatory repair functions

Monocyte-derived macrophages originate outside the brain and can be recruited when repair is required. Once recruited, they can display scavenging and inflammation-resolving properties that are distinct from resident microglia. This provides the biological rationale for therapeutically mobilizing peripheral immunity rather than simply suppressing inflammation inside the brain.

Sources: Shechter et al., PLoS Medicine, 2009; additional CNS-repair studies summarized in the Science deck.

05 | Why anti-PD-L1

Use an immune checkpoint as a temporary switch

The PD-1/PD-L1 pathway restrains T-cell activity. Transient checkpoint blockade can briefly release that brake and initiate a coordinated peripheral repair response.

PD-1/PD-L1 blockade transiently activates peripheral T cells
A short immune pulse can precede delayed, lasting cognitive benefit

The goal is not chronic immune activation. Preclinical work showed that a brief checkpoint-blocking signal can trigger downstream events that outlast antibody exposure. In this model, anti-PD-L1 acts as an instructor: it initiates the immune cascade, while recruited cells execute the repair response in the CNS.

Sources: Baruch et al., Nature Medicine, 2016; Immunobrain preclinical program.

06 | Mechanistic proof

The anti-PD-L1 effect depends on monocyte recruitment

Checkpoint blockade promotes brain homing of monocytes and Tregs, and blocking the monocyte recruitment pathway removes the therapeutic effect.

Anti-PD-L1 promotes monocyte and Treg homing
Blocking CCR2 abrogates effects on behavior, pathology, neuronal survival and inflammation

This is a critical mechanistic link: the response is not explained simply by peripheral T-cell activation. CCR2-dependent monocyte recruitment is required for the downstream CNS effects, identifying monocyte-derived macrophages as key mediators of the therapeutic cascade.

Sources: Ben-Yehuda et al., Molecular Neurodegeneration, 2021; Raposo et al., Journal of Neuroscience, 2014.

07 | TREM2 independence

The repair response can operate despite TREM2 deficiency

A major implication of the macrophage-driven mechanism is that benefit is not dependent on intact TREM2 signaling in resident microglia.

In 5xFAD models, anti-PD-L1 improved behavioral outcomes in both Trem2+/+ and Trem2-/- backgrounds. Together with the CCR2 experiments, this supports a model in which recruited monocyte-derived macrophages can provide a complementary repair pathway when resident microglial function is compromised.

Sources: Dvir-Szternfeld, Castellani, Arad et al. & Schwartz, Nature Aging, 2022.

08 | What happens inside the brain

Recruited macrophages remodel the inflammatory environment

The downstream response includes clearance of senescent microglia, reduced inflammatory signaling and preservation of synaptic function.

Systemic anti-PD-L1 reduces senescent microglia in a monocyte-dependent manner
Reduced astrogliosis/inflammatory cytokines with synaptic rescue

These findings connect the peripheral immune trigger to the CNS outcome: recruited immune cells alter the microglial landscape and help resolve chronic neuroinflammation, followed by downstream effects on synaptic and neuronal integrity.

Sources: Rachmian et al. & Schwartz, Nature Neuroscience, 2024; Rosenzweig et al. & Schwartz, Nature Communications, 2019.

09 | Translation into IBC-Ab002

IBC-Ab002 is engineered around this biology

A fully human anti-PD-L1 designed for transient, controlled peripheral immune activation rather than continuous checkpoint inhibition.

IBC-Ab002 combines high-affinity PD-L1 binding with Fc modification eliminating ADCC/CDC and a short half-life designed to limit prolonged systemic exposure. The therapeutic concept is intermittent dosing: a short peripheral immune signal that initiates a longer-lived repair response.

Sources: Immunobrain corporate scientific deck, October 2026.

10 | Integrated mechanism of action

Peripheral antibody activity → immune-cell trafficking → CNS repair

The antibody starts the cascade outside the brain; the downstream biological effect is carried by the immune response.

In preclinical mouse models of amyloid and tau pathology, anti-PD-L1-mediated recruitment of monocyte-derived macrophages was associated with improved learning and memory and disease-relevant behavioural outcomes where assessed (Rosenzweig et al., Nature Communications, 2019; Dvir-Szternfeld et al., Nature Aging, 2022). CCR2-blockade experiments support the requirement for monocyte recruitment in the downstream therapeutic response (Ben-Yehuda et al., Molecular Neurodegeneration, 2021). These findings link the immune repair mechanism to functional outcomes in the models studied; they do not demonstrate cognitive or clinical symptom improvement in patients.

Sources: Baruch et al., Nature Medicine, 2016; Rosenzweig et al., Nature Communications, 2019; Ben-Yehuda et al., Molecular Neurodegeneration, 2021; Dvir-Szternfeld et al., Nature Aging, 2022; Rachmian et al., Nature Neuroscience, 2024.

In summary

  1. 1

    Transient PD-L1 blockade activates peripheral immunity

  2. 2

    Monocytes and Tregs are recruited

  3. 3

    Monocyte-derived macrophages reach the CNS

  4. 4

    Senescent/dysfunctional microglia and neuroinflammation are reduced

  5. 5

    Synaptic and neuronal protection follows

The mechanism is macrophage-dependent, CCR2-dependent and can operate independently of TREM2.

Explore the pipeline All publications

References

  1. Baruch, Deczkowska et al., Science, 2014.
  2. Baruch et al., Nature Medicine, 2016.
  3. Ben-Yehuda et al., Molecular Neurodegeneration, 2021.
  4. Castellani, Croese, Peralta Ramos & Schwartz, Science, 2023.
  5. Croese, Castellani & Schwartz, Nature Immunology, 2021.
  6. Deczkowska et al., Nature Communications, 2017.
  7. Dvir-Szternfeld, Castellani, Arad et al. & Schwartz, Nature Aging, 2022.
  8. Rachmian et al. & Schwartz, Nature Neuroscience, 2024.
  9. Raposo et al., Journal of Neuroscience, 2014.
  10. Rosenzweig et al. & Schwartz, Nature Communications, 2019.
  11. Schwartz et al., Neuron, 2022.
  12. Shechter et al., PLoS Medicine, 2009.