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Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys

DOI: 10.1126/scitranslmed.aay1359 DOI Help

Authors: Mihalis S. Kariolis (Denali Therapeutics Inc) , Robert C. Wells (Denali Therapeutics Inc) , Jennifer A. Getz (Denali Therapeutics Inc) , Wanda Kwan (Denali Therapeutics Inc) , Cathal S. Mahon (Denali Therapeutics Inc) , Raymond Tong (Denali Therapeutics Inc) , Do Jin Kim (Denali Therapeutics Inc) , Ankita Srivastava (Denali Therapeutics Inc) , Catherine Bedard (Denali Therapeutics Inc) , Kirk R. Henne (Denali Therapeutics Inc) , Tina Giese (Denali Therapeutics Inc) , Victoria A. Assimon (Denali Therapeutics Inc) , Xiaocheng Chen (Denali Therapeutics Inc) , Yin Zhang (Denali Therapeutics Inc) , Hilda Solanoy (Denali Therapeutics Inc) , Katherine Jenkins (Denali Therapeutics Inc) , Pascal E. Sanchez (Denali Therapeutics Inc) , Lesley Kane (Denali Therapeutics Inc) , Takashi Miyamoto (Denali Therapeutics Inc) , Kylie S. Chew (Denali Therapeutics Inc) , Michelle E. Pizzo (Denali Therapeutics Inc) , Nicholas Liang (Denali Therapeutics Inc) , Meredith E. K. Calvert (Denali Therapeutics Inc) , Sarah L. Devos (Denali Therapeutics Inc) , Sulochanadevi Baskaran (Denali Therapeutics Inc) , Sejal Hall (Denali Therapeutics Inc) , Zachary K. Sweeney (Denali Therapeutics Inc) , Robert G. Thorne (Denali Therapeutics Inc) , Ryan J. Watts (Denali Therapeutics Inc) , Mark S. Dennis (Denali Therapeutics Inc) , Adam P. Silverman (Denali Therapeutics Inc) , Y. Joy Yu Zuchero (Denali Therapeutics Inc)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Science Translational Medicine , VOL 12

State: Published (Approved)
Published: May 2020

Open Access Open Access

Abstract: Effective delivery of protein therapeutics to the central nervous system (CNS) has been greatly restricted by the blood-brain barrier (BBB). We describe the development of a BBB transport vehicle (TV) comprising an engineered Fc fragment that exploits receptor-mediated transcytosis for CNS delivery of biotherapeutics by binding a highly expressed brain endothelial cell target. TVs were engineered using directed evolution to bind the apical domain of the human transferrin receptor (hTfR) without the use of amino acid insertions, deletions, or unnatural appendages. A crystal structure of the TV-TfR complex revealed the TV binding site to be away from transferrin and FcRn binding sites, which was further confirmed experimentally in vitro and in vivo. Recombinant expression of TVs fused to anti–β-secretase (BACE1) Fabs yielded antibody transport vehicle (ATV) molecules with native immunoglobulin G (IgG) structure and stability. Peripheral administration of anti-BACE1 ATVs to hTfR-engineered mice and cynomolgus monkeys resulted in substantially improved CNS uptake and sustained pharmacodynamic responses. The TV platform readily accommodates numerous additional configurations, including bispecific antibodies and protein fusions, yielding a highly modular CNS delivery platform.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 10/06/2020 09:19


Discipline Tags:

Life Sciences & Biotech Biophysics Health & Wellbeing Drug Delivery Neurology Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)