Zhu Q; McLellan JS; Kallewaard NL; Ulbrandt ND; Palaszynski S; Zhang J; Moldt B; Khan A; Svabek C; McAuliffe JM; Wrapp D; Patel NK; Cook KE; Richter BWM; Ryan PC; Yuan AQ; Suzich JA
A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants.
Published 2017 in Sci Transl Med, 9:
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.
1 - 1 of 1 carbohydrate structure entries
Structure entry #298: Man-9 N-glycan linked to Asn
a-D-Manp-(1-2)-a-D-Manp-(1-6)+
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a-D-Manp-(1-6)+
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a-D-Manp-(1-2)-a-D-Manp-(1-3)+ b-D-Manp-(1-4)-b-D-GlcpNAc-(1-4)-b-D-GlcpNAc-(1-4)-Asn
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a-D-Manp-(1-2)-a-D-Manp-(1-2)-a-D-Manp-(1-3)+