Fc-engineered large molecules targeting blood-brain barrier transferrin receptor and CD98hc have distinct central nervous system and peripheral biodistribution
Blood brain barrier-crossing molecules targeting transferrin receptor (TfR) and CD98 heavy chain (CD98hc) are widely reported to promote enhanced brain delivery of therapeutics. Here, we provide a comprehensive and unbiased biodistribution characterization of TfR and CD98hc antibody transport vehicles (ATV<sup>TfR</sup> and ATV<sup>CD98hc</sup>) compared to control IgG. Mouse whole-body tissue clearing reveals distinct organ localization for each molecule. In the brain, ATV<sup>TfR</sup> and ATV<sup>CD98hc</sup> achieve enhanced exposure and parenchymal distribution even when brain exposures are matched between ATV and control IgG in bulk tissue. Using a combination of cell sorting and single-cell RNAseq, we reveal that control IgG is nearly absent from parenchymal cells and is distributed primarily to brain perivascular and leptomeningeal cells. In contrast, ATV<sup>TfR</sup> and ATV<sup>CD98hc</sup> exhibit broad and unique parenchymal cell-type distribution. Finally, we profile in detail brain region-specific biodistribution of ATV<sup>TfR</sup> in cynomolgus monkey brain and spinal cord. Taken together, this in-depth multiscale characterization will guide platform selection for therapeutic targets of interest.
Authors
- Elysia Roche
- Yinhan Zhou
- Robert G. Thorne (ORCID: https://orcid.org/0000-0002-1671-5700)
- Mihail Ivilinov Todorov (ORCID: https://orcid.org/0000-0002-8627-1260)
- Thomas Sandmann (ORCID: https://orcid.org/0000-0002-6601-8890)
- David Joy (ORCID: https://orcid.org/0000-0001-9941-9538)
- Claire B. Discenza
- Y. Joy Yu Zuchero (ORCID: https://orcid.org/0000-0001-5183-7968)
- Amy Leung (ORCID: https://orcid.org/0000-0002-5175-430X)
- Nathalie Khoury
- David Tatarakis (ORCID: https://orcid.org/0000-0001-6297-2321)
- Joseph Duque (ORCID: https://orcid.org/0000-0002-0709-6071)
- Jason C. Dugas (ORCID: https://orcid.org/0000-0003-0849-9830)
- Roni Chau (ORCID: https://orcid.org/0000-0003-4861-563X)
- Johann Chow (ORCID: https://orcid.org/0009-0001-8170-6392)
- Doris Kaltenecker (ORCID: https://orcid.org/0000-0002-4110-1006)
- Yaneth Robles‐Colmenares (ORCID: https://orcid.org/0000-0001-8165-3406)
- Matthew Simon (ORCID: https://orcid.org/0000-0002-0065-6486)
- Ali Ertürk (ORCID: https://orcid.org/0000-0001-5163-5100)
- Moritz Negwer (ORCID: https://orcid.org/0000-0002-4470-6641)
- Lily Sarrafha (ORCID: https://orcid.org/0000-0002-6168-2119)
- Kylie S. Chew (ORCID: https://orcid.org/0000-0003-4752-009X)
- Allisa Clemens
- Michelle E. Pizzo (ORCID: https://orcid.org/0000-0003-4219-5996)
- Joseph W. Lewcock (ORCID: https://orcid.org/0000-0003-3012-7881)
- Gabrielly Lunkes de Melo (ORCID: https://orcid.org/0009-0002-1342-3080)
- Arash Moshkforoush (ORCID: https://orcid.org/0000-0003-4572-8911)
- Meredith Calvert (ORCID: https://orcid.org/0000-0003-2893-959X)
- Darren Chan (ORCID: https://orcid.org/0000-0002-7913-9325)
- Kaitlin Xa
- Connie Ha (ORCID: https://orcid.org/0000-0003-1257-2025)
- Mabel Tong
- Holly Kane
- Edwin I. Lozano
Institutions
- Denali Therapeutics (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-20
- DOI
- https://doi.org/10.1038/s41467-025-57108-x
- Citations
- 43
- Primary Topic
- Adenosine and Purinergic Signaling
- Type
- article
- Field-Weighted Citation Impact
- 48.06
Funders
- Denali Therapeutics