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Name: DNL919
Synonyms: TAK-920, ATV:TREM2
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Denali Therapeutics Inc., Takeda Pharmaceutical Company


This is a TREM2 agonist antibody that activates microglia to phagocytose amyloid. DNL919 contains a transferrin-receptor binding sequence engineered into its Fc domain. Thus, the antibody binds to the abundant transferrin receptors on endothelial cells of the blood-brain barrier, which facilitate its active transport into the brain.  

Although Denali initially provided proof of concept for its antibody transfer vehicle (ATV) technology using BACE-1 antibodies, the company is focusing development on the TREM2 antibody and other payloads (e.g., Kariolis et al., 2020; Ullman et al., 2020; DNL593). Takeda is partnering on the development of DNL919.

In preclinical work, the mouse version of this antibody was shown to promote TREM2 receptor signaling, increase microglia survival and Aβ phagocytosis, and enhance plaque clearance in a mouse model of amyloidosis (Schlepckow et al., 2020). DNL919 boosted brain microglial activity and glucose metabolism in the 5XFAD mouse model of Alzheimer’s. In mice, the antibody achieved sixfold higher brain entry, and was more efficient at activating TREM2 than a non-ATV version (van Lengerich et al., 2023).


In January 2022, the FDA placed a clinical hold on Denali’s investigational new drug application for DNL919 in the U.S., pending clarification of questions regarding the preclinical toxicology, clinical trial protocol, informed consent form, and investigator brochure (press releaseSEC disclosure).

In July 2022, Denali began a Phase 1 study in the Netherlands, to assess safety, tolerability, pharmacokinetics, and target engagement after single ascending doses of DNL919 in 80 healthy participants. The trial is expected to be completed in July 2023.

For details on this trial, see

Last Updated: 20 Jan 2023


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Therapeutics Citations

  1. DNL593

Paper Citations

  1. . Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys. Sci Transl Med. 2020 May 27;12(545) PubMed.
  2. . Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice. Sci Transl Med. 2020 May 27;12(545) PubMed.
  3. . Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol Med. 2020 Apr 7;12(4):e11227. Epub 2020 Mar 10 PubMed.
  4. . A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models. Nat Neurosci. 2023 Mar;26(3):416-429. Epub 2023 Jan 12 PubMed.

External Citations

  1. press release
  2. SEC disclosure

Further Reading