A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants

被引：252

作者：

Zhu, Qing ^{[1
]}

McLellan, Jason S. ^{[2
]}

Kallewaard, Nicole L. ^{[1
]}

Ulbrandt, Nancy D. ^{[1
]}

Palaszynski, Susan ^{[1
]}

Zhang, Jing ^{[1
]}

Moldt, Brian ^{[1
]}

Khan, Anis ^{[3
]}

Svabek, Catherine ^{[1
]}

McAuliffe, Josephine M. ^{[1
]}

Wrapp, Daniel ^{[2
]}

Patel, Nita K. ^{[1
]}

Cook, Kimberly E. ^{[4
]}

Richter, Bettina W. M. ^{[1
]}

Ryan, Patricia C. ^{[5
]}

Yuan, Andy Q. ^{[4
]}

Suzich, JoAnn A. ^{[1
]}

机构：

[1] MedImmune LLC, Dept Infect Dis, One MedImmuneWay, Gaithersburg, MD 20878 USA

[2] Geisel Sch Med Dartmouth, Dept Biochem & Cell Biol, 7200 Vail Bldg, Hanover, NH 03755 USA

[3] MedImmune LLC, Dept Clin Pharmacol & Drug Metabol & Pharmacokine, One MedImmune Way, Gaithersburg, MD 20878 USA

[4] MedImmune LLC, Dept Antibody Discovery & Prot Engn, One MedImmune Way, Gaithersburg, MD 20878 USA

[5] MedImmune LLC, Biol Safety Assessment, One MedImmune Way, Gaithersburg, MD 20878 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2017年 / 9卷 / 388期

关键词：

RESPIRATORY-SYNCYTIAL-VIRUS; HUMANIZED MONOCLONAL-ANTIBODY; NEONATAL FC-RECEPTOR; ENHANCED DISEASE; IN-VITRO; INFECTION; FUSION; BRONCHIOLITIS; PALIVIZUMAB; INFLUENZA;

D O I：

10.1126/scitranslmed.aaj1928

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Prevention of respiratory syncytial virus (RSV) illness in all infants is a major public health priority. However, no vaccine is currently available to protect this vulnerable population. Palivizumab, the only approved agent for RSV prophylaxis, is limited to high-risk infants, and the cost associated with the requirement for dosing throughout the RSV season makes its use impractical for all infants. We describe the development of a monoclonal antibody as potential RSV prophylaxis for all infants with a single intramuscular dose. MEDI8897*, a highly potent human antibody, was optimized from antibody D25, which targets the prefusion conformation of the RSV fusion (F) protein. Crystallographic analysis of Fab in complex with RSV F from subtypes A and B reveals that MEDI8897* binds a highly conserved epitope. MEDI8897* neutralizes a diverse panel of RSV A and B strains with >50-fold higher activity than palivizumab. At similar serum concentrations, prophylactic administration of MEDI8897* was ninefold more potent than palivizumab at reducing pulmonary viral loads by >3 logs in cotton rats infected with either RSV A or B subtypes. MEDI8897 was generated by the introduction of triple amino acid substitutions (YTE) into the Fc domain of MEDI8897*, which led to more than threefold increased half-life in cynomolgus monkeys compared to non-YTE antibody. Considering the pharmacokinetics of palivizumab in infants, which necessitates five monthly doses for protection during an RSV season, the high potency and extended half-life of MEDI8897 support its development as a cost-effective option to protect all infants from RSV disease with once-per-RSV-season dosing in the clinic.

引用

页数：11

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