OncoC4, Inc. has unveiled compelling preclinical data demonstrating the therapeutic potential of ONC-841, a first-in-class anti-SIGLEC 10 monoclonal antibody, in treating Alzheimer's disease (AD). The findings, presented at the 2025 Alzheimer's Association International Conference in Toronto, reveal that ONC-841 significantly reduced amyloid plaques, normalized microglia function, and improved memory in preclinical mouse models.
Novel Target Identification
The research identified SIGLEC 10 as a genetic driver for amyloid plaque formation in mice, marking a significant breakthrough in understanding Alzheimer's pathogenesis. According to the study data, transgenic mice carrying the unmutated human SIGLEC 10 gene cluster developed amyloid plaques, representing what researchers believe is the first mouse model where a single, unmutated human gene cluster induces Aβ plaque formation—a critical hallmark of AD.
"SIGLEC 10-CD24 pathway, an innate immune checkpoint discovered by the cofounders, is implicated in cancer evasion of host immunity, which OncoC4 has been exploring for cancer treatment," said Yang Liu, PhD, Co-Founder, Chief Executive Officer, and Chief Scientific Officer of OncoC4. "These compelling preclinical findings from two AD models highlight the potential of ONC-841 as a first-in-class immunotherapy for neurodegeneration."
Therapeutic Mechanisms and Efficacy
The preclinical studies demonstrated multiple therapeutic benefits of ONC-841 treatment. Key findings include SIGLEC 10 blockade in brain microglia at therapeutic doses, enhanced microglia migration and phagocytosis of amyloid plaques, and significant reduction in hallmarks of AD, including brain amyloid burden and pTau plasma levels. The treatment also normalized microglia morphology and provided functional benefits including improved memory and learning activities.
In the transgenic mouse model, researchers found that the human SIGLEC 10 gene was expressed exclusively in brain microglia, and microglia from these transgenic mice showed reduced uptake of Aβ fibrils and pTau tangles. Importantly, SIGLEC 10 expression induced Aβ plaques in mouse brain even in the absence of other known mutations in AD genes, and ONC-841 treatment successfully reduced these SIGLEC 10-induced Aβ plaques.
Clinical Development and Dual Applications
ONC-841 is currently under clinical development for both solid tumors and Alzheimer's disease, representing a unique dual-indication approach. Dr. Liu noted that the therapy builds on "the strong safety profile and promising early efficacy from our dose-escalation ONC-841-002 study in solid tumors (NCT06352359)."
The findings support a causal relationship between SIGLEC 10 and pathogenesis of late-onset AD, which typically differs from early-onset AD that is associated with known pathogenic mutations in APP, PS1, or PS2 genes. This distinction positions ONC-841 as a potentially transformative treatment for the more common late-onset form of the disease.
Research Implications
The research establishes SIGLEC 10 as playing a likely causal role in AD pathogenesis and other neurodegenerative diseases through increased levels of amyloid beta plaques in the brain. The data were presented in two poster presentations at AAIC: "Therapeutic Activities of ONC-841, an Anti-human SIGLEC 10 mAb, in Multiple Transgenic Mouse AD Models" and "Mice Carrying Unmutated Human SIGLEC 10 Gene Cluster Transgene Develop Amyloid Plaques: A Model for Late Onset AD."
OncoC4, based in Rockville, Maryland, is a late-stage biopharmaceutical company focused on developing novel medicines for cancer and immunological diseases. The company's pipeline includes other assets such as AI-081, a bispecific antibody targeting PD-1 and VEGF currently in Phase 1/2 trials, and a strategic collaboration with BioNTech for gotistobart (BNT316/ONC-392), an anti-CTLA-4 antibody in pivotal trials for squamous non-small cell lung cancer.
