Molecular mechanism of action of a blood brain barrier shuttle antibody
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The transferrin receptor has emerged as a prime target for transcytosis of antibody shuttles from the bloodstream into the brain parenchyma to deliver therapeutic payloads that treat neurological disorders. However, how the transferrin receptor-antibody binding mode impacts avidity, degradation, pH sensitivity and delivery remains underexplored. To address this, we determined the cryo-EM structure of mouse transferrin receptor 1 bound to the model brain shuttle antibody 8D3. In combination with cell binding and localisation studies we show that 8D3 can structurally support small-scale inter-receptor cross-linking, such as in self-contained pairs, that cause avidity but do not induce receptor redistribution or degradation. The structure can also explain pH-dependent binding modes, and we show how some of these antibody variants with graded sensitivities regulate brain penetration in vivo . Overall, our study illuminates how distinct molecular features of antibody binding impact transferrin receptor behaviour and brain delivery to inform on future shuttle design.
