Targeting soluble TNF to attenuate neuroinflammation in Alzheimer’s disease

Raymond J. Tesi, MD, INmune Bio, Boca Raton, FL, outlines the rationale behind the development of XPro1595: a protein biologic that targets soluble TNF (sTNF) under investigation in Alzheimer’s disease (AD). The approach is based on evidence that suggests neuroinflammation is one of the prime drivers of neurodegeneration and cognitive decline. Genome wide association studies have identified many risk genes significantly associated with Alzheimer’s disease that are related to the immune response and microglia. Erroneous activation of microglia and astrocytes has been associated with compromised synaptic and neuronal viability. Therefore, targeting neuroinflammation may have important implications for neurodegeneration in AD. XPro1595 selectively targets sTNF, a major inflammatory marker tied to AD. By avoiding transmembrane TNF, it is thought that the innate and adaptive immune responses can be normalized while the brain retains capacity for remodeling and repair. A Phase I trial has shown that XPro1595 reduces neuroinflammation, improves synaptic function, and aids axonal regeneration. Dr Tesi emphasizes the importance of enriching studies with patients most likely to benefit from the strategy under investigation. Ongoing trials of XPro1595 will only enroll patients with biomarkers of inflammation in their blood. This interview took place at the Alzheimer's Association International Conference (AAIC) 2022 in San Diego, CA