Company: DNLI
Filing Date: 2025-02-27
Form Type: 10-K
Source: 0001714899-25-000066
Chunk: 114

Company: Denali Therapeutics Inc.
Filing Date: 2025-02-27
Form: 10-K
Item: Item 1
Chunk 114
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 BBB is essential for our survival, it also prevents the delivery of medicines to the brain in sufficient quantities to have therapeutic effect. We have pioneered and are developing a new class of biotherapeutics to directly address the BBB challenge. 

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We invented, developed, and continue to optimize a proprietary technology, called the TransportVehicleTM ("TV"), to deliver our large molecule biotherapeutic candidates to the brain after systemic administration. Clinical and preclinical studies with several of our TV-enabled product candidates demonstrated high concentrations and broad distribution in all explored regions of the CNS and in key CNS cell types and showed improved pharmacodynamic effects compared to standard biotherapeutics. We believe that the TV can significantly increase the probability of success of biotherapeutics for CNS indications and can enable many new effective medicines.

Our TV technology is modular and enables several classes of biotherapeutics to more effectively cross the BBB, including enzymes, antibodies, oligonucleotides, and other proteins. The TV technology is engineered to engage specific BBB transport receptors, such as the transferrin receptor ("TfR") and CD98 heavy chain ("CD98hc"), which are highly expressed in brain capillaries and facilitate transport of proteins into the brain (Figure 1) in a process called receptor mediated transcytosis.

Figure 1: Engineering brain delivery. Schematic of the TV platform and modalities, designed to cross the BBB through receptor mediated transcytosis, leveraging endogenous receptors expressed on endothelial cells of the central nervous system vasculature.

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Our TV technology is differentiated from other BBB technologies through its engineering approach, which may provide superior therapeutic efficacy, safety, and tolerability through higher stability, exposure, and biodistribution as well as the potential for lower immunogenicity of drug candidates in the brain. Compared to conventional approaches that use the Fab portion (the "arms") of a full-length antibody to bind to the targeted BBB receptor (e.g.,TfR), we use an Fc domain (the "legs") (Figure 2). We have engineered the BBB receptor binding site into one of the Fc's (monovalent binding) and we can optimize binding affinity (how tightly the Fc binds its BBB receptor target) to enhance brain delivery and limit receptor degradation. We can also modify the amino acid sequences in the Fc to enable "conditional effector function", which is important for optimal activity of certain molecules, such as ATV:Abeta, that require immune cell activity for therapeutic effect. By toggling effector function