CD98hc-targeted antibody shuttles for central nervous system delivery with broad cross-species reactivity
An active learning strategy for developing CD98hc-targeted CNS shuttles begins with an antibody that binds human and cynomolgus monkey CD98hc and evolves it to also recognize a rodent orthologue, reducing differences in
Bispecific antibodies targeting the blood–brain barrier are being used to increase the therapeutic potential of IgGs and other biologics. However, antibodies specific for human BBB targets, such as CD98hc or transferrin receptor 1 (TfR1), typically lack cross-reactivity with orthologues from species commonly used in preclinical testing, like mouse or cynomolgus monkey (cyno). Researchers have addressed this limitation by using an active learning method to isolate anti-CD98hc antibodies with broad species cross-reactivity. The approach starts from a fully human antibody that binds human and cynomolgus monkey CD98hc but lacks binding to mouse CD98hc. Through iterative mutagenesis and library optimization, the researchers evolved the antibody to recognize mouse, cyno, and human CD98hc with similar affinities. These CD98hc-targeted CNS shuttles are expected to accelerate clinical translation by eliminating the need for transgenic animals or surrogate antibodies.