The blood–brain barrier (BBB) presents a major obstacle to the use of conventional antibodies in treating neurological conditions. One promising strategy leverages receptor-mediated transcytosis (RMT), in which therapeutic cargo is directed to receptors on brain endothelial cells to facilitate transport across the BBB. Transferrin receptor 1 (TfR1) is a well-established target for this approach due to its validated transport properties. To support this strategy, Adimab scientists developed a diverse panel of TfR1-binding antibodies designed to enable efficient BBB transport while preserving transferrin binding and compatibility with multispecific formats. 

Approach and outcomes 

• A panel of 69 TfR1-targeting antibodies (IgG and HCAb) were generated, targeting human TfR1 across a range of monovalent binding affinities. Of these, 66 do not compete with transferrin binding, and binning against benchmark antibodies confirmed diverse epitope coverage. 

• Seven lineages (IgG and HCAb) were optimized to improve human–cynomolgus TfR1 cross-reactivity and provide a range of affinities while maintaining favorable developability characteristics. 

• Four optimized antibodies were converted into 2+1 multispecific antibodies using Adimab's heterodimerization technologies. These multispecifics showed rapid internalization in a brain endothelial cell line (hCMEC/D3). 

• In a humanized TfR1 mouse model, the multispecific antibodies demonstratedbrain accumulation compared to a negative control and at levels comparable to a clinically validated TfR1 benchmark. 

Why it matters 

These results establish a versatile TfR1 antibody panel that addresses key barriers to CNS delivery. The antibodies combine non-competitive transferrin binding, species cross-reactivity, and efficient internalization, enabling their integration into multispecific formats that achieve brain exposure comparable to validated transport systems. 

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