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

被引：235

作者：

Kariolis, Mihalis S. ^{[1
]}

Wells, Robert C. ^{[1
]}

Getz, Jennifer A. ^{[1
]}

Kwan, Wanda ^{[1
]}

Mahon, Cathal S. ^{[1
]}

Tong, Raymond ^{[1
]}

Kim, Jin ^{[1
]}

Srivastava, Ankita ^{[1
]}

Bedard, Catherine ^{[1
]}

Henne, Kirk R. ^{[1
]}

Giese, Tina ^{[1
]}

Assimon, Victoria A. ^{[1
]}

Chen, Xiaocheng ^{[1
]}

Zhang, Yin ^{[1
]}

Solanoy, Hilda ^{[1
]}

Jenkins, Katherine ^{[1
]}

Sanchez, Pascal E. ^{[1
]}

Kane, Lesley ^{[1
]}

Miyamoto, Takashi ^{[1
]}

Chew, Kylie S. ^{[1
]}

Pizzo, Michelle E. ^{[1
]}

Liang, Nicholas ^{[1
]}

Calvert, Meredith E. K. ^{[1
]}

DeVos, Sarah L. ^{[1
]}

Baskaran, Sulochanadevi ^{[1
]}

Hall, Sejal ^{[1
,2
]}

Sweeney, Zachary K. ^{[1
]}

Thorne, Robert G. ^{[1
]}

Watts, Ryan J. ^{[1
]}

Dennis, Mark S. ^{[1
]}

Silverman, Adam P. ^{[1
]}

Zuchero, Y. Joy Yu ^{[1
]}

机构：

[1] Denali Therapeut Inc, 161 Oyster Point Blvd, San Francisco, CA 94080 USA

[2] Audentes Therapeut, 600 Calif St, San Francisco, CA 94108 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2020年 / 12卷 / 545期

关键词：

TRANSFERRIN RECEPTOR; STRUCTURAL LOOPS; DRUG-DELIVERY; ANTIBODY; IMMUNOGLOBULIN; DOMAINS; TRANSCYTOSIS; DIFFUSION; NERVE;

D O I：

10.1126/scitranslmed.aay1359

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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-beta-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.

引用

页数：13

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