RT Journal Article
SR Electronic
T1 A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaaj1928
DO 10.1126/scitranslmed.aaj1928
VO 9
IS 388
A1 Zhu, Qing
A1 McLellan, Jason S.
A1 Kallewaard, Nicole L.
A1 Ulbrandt, Nancy D.
A1 Palaszynski, Susan
A1 Zhang, Jing
A1 Moldt, Brian
A1 Khan, Anis
A1 Svabek, Catherine
A1 McAuliffe, Josephine M.
A1 Wrapp, Daniel
A1 Patel, Nita K.
A1 Cook, Kimberly E.
A1 Richter, Bettina W. M.
A1 Ryan, Patricia C.
A1 Yuan, Andy Q.
A1 Suzich, JoAnn A.
YR 2017
UL http://stm.sciencemag.org/content/9/388/eaaj1928.abstract
AB The common respiratory syncytial virus (RSV) can progress to a very dangerous lower respiratory infection in some infants. A protective monoclonal antibody is available but is not recommended for general use. Zhu et al. describe the selection and optimization of a human monoclonal antibody able to neutralize a wide array of RSV A and B viruses and protect cotton rats at lower doses than the currently approved antibody. The antibody was optimized to persist in circulation, and data indicate that infants could be given a single dose and be protected for the entirety of the RSV season. If administered widely, this antibody could potentially prevent the hospitalization of thousands of children each year.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.