Science Advances study shows that modulating PD-L1 in the brain restores microglial homeostatic function and reduces neuronal hyperactivity, supporting the biological rationale for IMNEWRUN's BBB-penetrating INR301 program

SUWON, South Korea, September 22, 2026 — IMNEWRUN Inc. today announced that a joint study with the laboratory of Professor Minah Suh at Sungkyunkwan University (SKKU) and the laboratory of Professor Ho-Keun Kwon at Yonsei University College of Medicine has shown that modulating the immune checkpoint protein PD-L1 in the brain restores microglial homeostatic function and reduces aberrant neuronal hyperactivity in a mouse model of Alzheimer's disease. The study, which provides a mechanistic basis for a new Alzheimer's therapeutic strategy aimed at restoring brain immune balance, was published in Science Advances on September 18, 2026 (U.S. Eastern Time).

The research originated from observations and therapeutic hypotheses that emerged during IMNEWRUN's work on INR301, its blood–brain barrier (BBB)-penetrating antibody candidate targeting PD-L1. Under the industry–academia collaboration between IMNEWRUN and SKKU, the team of Professor Suh—an IMNEWRUN co-founder in SKKU's Department of Global Biomedical Engineering—worked with Professor Kwon's team to dissect the mechanism of PD-L1 modulation in the brain, using cell-type-specific control of gene expression and in vivo imaging.

In Alzheimer's disease, dysfunction of the glial cells that maintain the brain's microenvironment—including microglia and astrocytes—plays an important role alongside amyloid-beta accumulation and tau pathology. Microglia, the brain's resident immune cells, sense damage signals in their surroundings and help regulate neuronal activity; when these homeostatic functions decline, the interplay between the brain's immune environment and its neurons can fall out of balance.

PD-1 and PD-L1 are immune checkpoint proteins that regulate immune responses and have been studied primarily in cancer immunotherapy. Noting that PD-1 expression was elevated in microglia and PD-L1 expression in astrocytes of the Alzheimer's mouse model, the researchers examined how this signaling affects glial and neuronal function within the brain.

After administering an anti-PD-L1 antibody directly into the brains of the disease-model mice, the team used in vivo two-photon microscopy—which allows cellular activity to be observed in the living brain—to track functional changes. The convergence of microglial processes toward sites of injury was restored, and expression of P2RY12, a receptor associated with microglial homeostatic function, increased. Analysis of neuronal calcium signaling showed a reduction in aberrant hyperactivity.

Notably, selectively suppressing PD-L1 expression in astrocytes produced similar effects: microglial injury responses and P2RY12 expression were restored, and neuronal hyperactivity was reduced. These findings provide mechanistic evidence that astrocytic PD-L1 is involved in regulating microglial homeostasis and neuronal activity.

The recovery of microglial injury responses seen with direct brain administration was not observed under the systemic administration conditions tested in the study. This suggests that delivering the antibody to its target inside the brain may be critical for effectively modulating PD-L1 signaling.

Together, the results indicate that modulating PD-1/PD-L1 signaling in the brain to restore glial homeostatic function and glia–neuron interactions may represent a new therapeutic strategy for Alzheimer's disease. IMNEWRUN is developing INR301, designed with its BBB-penetration platform TRANSMAB to target PD-L1 within the brain, and the joint study supports the biological rationale behind the candidate's strategy of restoring brain immune balance.

"Observations and questions that arose in our therapeutic research led to precise mechanistic studies by our academic collaborators, giving us evidence that supports restoring brain immune balance as a therapeutic direction," said Han-Joo Kim, CEO of IMNEWRUN. "Building on these results, we will continue to advance INR301, which is designed to cross the BBB and target PD-L1 in the brain."

Publication
Title: Targeting glial PD-1/PD-L1 restores microglial homeostasis and reduces neuronal hyperactivity in an Alzheimer's disease model
Journal: Science Advances 12, eadx0731 (2026)
Publication date: September 18, 2026 (U.S. Eastern Time)
DOI: https://doi.org/10.1126/sciadv.adx0731