PLATFORM & PIPELINE
MOONSHOT means transformation of a huge idea that will change the future of human beings into reality, just as the imagination of human traveling to the moon has been realized through challenges. GAIA-Aβ is Illimis Therapeutics' great challenge to turn hopes of improving the quality of life of Alzheimer's Disease patients and families into reality, with the potential to address ARIA (Amyloid Related Imaging Abnormalities) issue which has been an unmet needs of existing Alzheimer's treatment.
Anti-inflammatory clearance of amyloid-β by a chimeric Gas6 fusion protein
Hyuncheol Jung, Se Young Lee, Seongjoon Lim, Hyeong Ryeol Choi, Yeseong Choi,
Minjin Kim, Segi Kim, Yujean Lee, Kyung Ho Han, Won-Suk Chung & Chan Hyuk Kim
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.
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.