Background: The blood-brain barrier (BBB) represents a major challenge for the development of monoclonal antibody of fusion portein based therapies for brain disorders. KHN923 is a bispecific antibody that has been developed for the purpose of crossing the BBB, intented to deliver targeted amyloid therapy for the treatment of Alzheimer's disease. The drug was engineered using Kanghong Pharmaceutical's "TFR Nanobody-Based Blood-Brain Barrier Penetration Platform" technology, which enhances its ability to traverse the BBB.

Methods: A nanobody capable of crossing the BBB was identified using an hTFR transgenic mouse model. The process of fusing this humanized nanobody to the Fc segment of Lecanemab resulted in the formation of the symmetrical KHN923. Its ability to phagocytose Aβ₄₂ protofibrils via Fc and TfR was compared with competitors. The BBB crossing capability of KHN923 was investigated in vivo. Utilising Alzheimer's disease mouse models that expresses hTfR, a comparative analysis was conducted on the BBB penetration and Aβ₄₂ protofibrils clearance capabilities of KHN923 and competitors. Result: KHN923 promotes cellular clearance of Aβ₄₂ protofibrils through Fc/FcγR activation of microglia and TFR receptor binding. In mouse models, this antibody has been shown to exhibit more than 100-fold greater efficiency than unmodified Lecanemab and 5-10 fold greater than Trontinemab in entering the brain and binding amyloid plaques. At doses significantly lower than the parent antibody, KHN923 has been shown to clean soluble Aβ₄₂ protofibrils in the brain more effectively than lecanemab and trontinemab.

Conclusion: Together, Our data demonstrate that KHN923 effectively crosses the blood-brain barrier and clears Aβ plaques.