A team of researchers at KAIST in South Korea says it has developed a novel fusion protein drug, αAβ-Gas6, which efficiently eliminates amyloid beta (Aβ) via an entirely different mechanism than Aβ antibody-based immunotherapy. In a mouse model of AD, αAβ-Gas6 not only removed Aβ with higher potency, but also circumvented the neurotoxic inflammatory side effects associated with conventional antibody treatments.
The research is important because Aduhelm, a monoclonal antibody targeting Aβ recently became the first FDA-approved drug for Alzheimer’s disease (AD) based on its ability to decrease Aβ plaque burden in AD patients. However, its effect on cognitive improvement is still controversial.
Moreover, about 40% of the patients treated with this antibody experienced serious side effects, including cerebral edemas (ARIA-E) and hemorrhages (ARIA-H) that are likely related to inflammatory responses in the brain when the Aβ antibody binds Fc receptors (FCR) of immune cells such as microglia and macrophages. These inflammatory side effects can cause neuronal cell death and synapse elimination by activated microglia, and even have the potential to exacerbate cognitive impairment in AD patients.
Thus, current Aβ antibody-based immunotherapy holds the inherent risk of doing more harm than good due to their inflammatory side effects.
The South Korean team’s different approach “Anti-inflammatory clearance of amyloid-β by a chimeric Gas6 fusion protein” is described in Nature Medicine.
“Clearing amyloid-β (Aβ) through immunotherapy is one of the most promising therapeutic approaches to Alzheimer’s disease (AD). Although several monoclonal antibodies against Aβ have been shown to substantially reduce Aβ burden in patients with AD, their effects on improving cognitive function remain marginal. In addition, a significant portion of patients treated with Aβ-targeting antibodies experience brain edema and microhemorrhage associated with antibody-mediated Fc receptor activation in the brain,” write the investigators.
“Here, we develop a phagocytosis inducer for Aβ consisting of a single-chain variable fragment of an Aβ-targeting monoclonal antibody fused with a truncated receptor binding domain of growth arrest-specific 6 (Gas6), a bridging molecule for the clearance of dead cells via TAM (TYRO3, AXL, and MERTK) receptors. This chimeric fusion protein (αAβ–Gas6) selectively eliminates Aβ plaques through TAM receptor-dependent phagocytosis without inducing NF-kB-mediated inflammatory responses or reactive gliosis.
“Furthermore, αAβ–Gas6 can induce synergistic clearance of Aβ by activating both microglial and astrocytic phagocytosis, resulting in better behavioral outcomes with substantially reduced synapse elimination and microhemorrhage in AD and cerebral amyloid angiopathy model mice compared with Aβ antibody treatment.
“Our results suggest that αAβ–Gas6 could be a novel immunotherapeutic agent for AD that overcomes the side effects of conventional antibody therapy.”
“FcR activation by Aβ targeting antibodies induces microglia-mediated Aβ phagocytosis, but it also produces inflammatory signals, inevitably damaging brain tissues,” said paper authors Chan Hyuk Kim, PhD, and Won-Suk Chung, PhD, associate professors in the department of biological sciences at KAIST.
“Therefore, we utilized efferocytosis, a cellular process by which dead cells are removed by phagocytes as an alternative pathway for the clearance of Aβ in the brain,” continued Kim and Chung. “Efferocytosis is accompanied by anti-inflammatory responses to maintain tissue homeostasis. To exploit this process, we engineered Gas6, a soluble adaptor protein that mediates efferocytosis via TAM phagocytic receptors in such a way that its target specificity was redirected from dead cells to Aβ plaques.”
By using a mouse model of cerebral amyloid angiopathy (CAA), a cerebrovascular disorder caused by the deposition of Aβ within the walls of the brain’s blood vessels, the team also showed that the intrathecal administration of Gas6 fusion protein significantly eliminated cerebrovascular amyloids, along with a reduction of microhemorrhages. These data demonstrate that aAb-Gas6 is a potent therapeutic agent in eliminating Aβ without exacerbating CAA-related microhemorrhages, according to the scientists.”
We believe our approach can be a breakthrough in treating AD without causing inflammatory side effects and synapse loss. Our approach holds promise as a novel therapeutic platform that is applicable to more than AD,” said Kim and Chung. “By modifying the target-specificity of the fusion protein, the Gas6-fusion protein can be applied to various neurological disorders as well as autoimmune diseases affected by toxic molecules that should be removed without causing inflammatory responses.”
The two professors have founded Illimis Therapeutics based on this strategy of designing chimeric Gas6 fusion proteins that would remove toxic aggregates from the nervous system. Through this company, they are planning to further develop various Gas6-fusion proteins not only for Aβ but also for Tau to treat AD symptoms.
To learn more about other advances in Alzheimer’s research, see GEN: “Alzheimers-and-Parkinsons-Disease-Genomes:-Scientists-Spot-Signatures-in-DNA-Repeats” and “Single-Cell-Functional-Proteome-Profiling-Uncovers-Novel-Targets-for-Alzheimers-Disease.”