Abstract A026: Discovery and development of a transferrin receptor antibody panel for efficient blood-brain barrier delivery as part of a multispecific antibody

Abstract Therapeutic delivery across the blood-brain barrier (BBB) remains a significant challenge in developing treatments for neurological diseases, particularly for protein-based therapeutics. One promising delivery approach utilizes receptor-mediated transcytosis (RMT). In this approach, therapeutics are targeted to a receptor present in the brain endothelia, typically via a secondary binding domain, which facilitates transport of the bound therapeutic. Transferrin receptor (TfR) and CD98 heavy chain (CD98HC) are two receptors that are attractive targets for this receptor-targeted BBB delivery. TfR has been a primary focus due to its well-characterized transport properties. Using a yeast-based antibody discovery platform, we have discovered and optimized a diverse panel of conventional (IgG) and single-domain antibodies (sdAbs) that target TfR. These antibodies show a range of binding affinities to TfR and do not compete with endogenous transferrin binding. The panel displays diverse epitope breadth and cross-reactivity between human and cynomolgus TfR. The panel exhibits rapid internalization in TfR-expressing Jurkat cells and in a brain endothelial cell line (hCMEC/D3). Finally, we have generated a panel of 2+1 multispecific antibodies containing two anti-BACE1 Fab arms and a C-terminal fusion of the anti-TfR binder (Fab or sdAb) for in vivo BBB permeability assessment using a humanized mouse TfR model. The 2+1 multispecifics showed improved uptake across the BBB compared to an anti-BACE1 antibody containing a non-TfR-binding C-terminal Fab. The TfR antibody panel developed here provides a novel toolset to aid in the development of complex multispecific antibodies across neurological indications. Citation Format: Nadthakarn Boland, Emma Cammack, Olivia Scheideler, John Martel, Robert Pejchal, Eric Krauland, Emily Radke, Kevin Schutz, Bradley M. Lunde. Discovery and development of a transferrin receptor antibody panel for efficient blood-brain barrier delivery as part of a multispecific antibody [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A026.