Grabody B, a Novel IGF-1 Receptor-Based Shuttle, Mediates Efficient Delivery of Biologics Across the Blood-Brain Barrier

Abstract

Delivering effective therapeutics to the brain is a great challenge. Molecular shuttles use receptors expressed on brain endothelial cells to deliver therapeutics. Currently, antibodies targeting transferrin receptor (TfR) have been widely developed as the molecular shuttle. However, TfR-based approach raised concerns about safety and developmental burden. Here, we report insulin growth factor 1 receptor (IGF1R) as an ideal target for the molecular shuttle. Further, we describe Grabody B, an antibody against the IGF1R as a novel molecular shuttle. Grabody B has broad cross-species reactivity and did not interfere with IGF1R-mediated signaling. Administration of Grabody B-fused therapeutic antibody induced better improvement in neuropathology and behavior than the therapeutic antibody alone in a Parkinson’s disease animal model, owing to its superior serum pharmacokinetics and enhanced brain exposure. Taken together, our study demonstrated IGF1R as an ideal shuttle target and Grabody B as a novel, safe and efficient molecular shuttle.